Macrocyclic compound and use thereof

ABSTRACT

Compounds represented by the following formula (I): 
     
       
         
         
             
             
         
       
     
     wherein each symbol in the formula is as described herein, or a salt thereof, and compositions comprising the same, and methods of using the same as an NRF2 activator and/or a preventive or therapeutic agent for diseases associated with oxidative stress, in particular, hepatic disease (for example, non-alcoholic steatohepatitis (NASH)), cardiovascular disease (for example, heart failure or pulmonary arterial hypertension), lung disease (for example, chronic obstructive pulmonary disease (COPD)), kidney disease (for example, chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system disease (for example, Parkinson&#39;s disease), mitochondrial disease (for example, Friedreich motor ataxia, mitochondrial myopathy), inflammatory disease (for example, multiple sclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease, cancer, or the like.

TECHNICAL FIELD

The present invention relates to a macrocyclic compound having anactivity of activating nuclear factor erythroid 2-related factor 2(herein, may be abbreviated as “NRF2”) and is expected to be useful intreatment for diseases associated with oxidative stress.

BACKGROUND ART

Oxidative stress refers to a condition where oxidation andanti-oxidation is out of balance and excessive oxidation reactionadversely affects organisms, and it has been clear that oxidative stressis closely related to various pathogeneses. A living body provides adefense mechanism against oxidative stress, and NRF2 (nuclear factorerythroid 2-related factor 2) plays a central role in this mechanism. Inthe steady state, NRF2 is bound to KEAP1 (Kelch-like ECH-associatedprotein 1) and its intracellular concentration is kept low throughdegradation regulation by proteasome. However, when receiving some kindof oxidative stress, NRF2 dissociates from KEAP1, translocates to theinside of nucleus, and binds to a transcriptional region called ARE(anti-oxidant response element), thereby inducing gene expression of avariety of anti-oxidative substances (activation of NRF2). TheNRF2-KEAP1 system is a biological defense mechanism for quicklyresponding to oxidative stress (Free Radical Biology and Medicine 201588: 362-372; Non Patent Literature 1). Accordingly, NRF2 activators areexpected to provide a strong anti-oxidative activity by activating theNRF2-KEAP1 system. Among NRF2 activators, there is one type thatmodifies a Cys residue of KEAP1, and there is another type that inhibitsthe protein-protein interaction of NRF2-KEAP1, but both have been knownto activate NRF2 (Med Res Rev. 2016 36(5): 924-63; Non Patent Literature2).

NRF2 activators are believed to exhibit effectiveness in prevention ortreatment for a variety of oxidative stress diseases. Specifically,examples of the diseases include hepatic disease (non-alcoholicsteatohepatitis (NASH) or the like), bile duct disease (primarysclerosing cholangitis (PSC) or the like), lung disease (obstructivepulmonary disease (COPD) or the like), kidney disease (chronic kidneydisease (CKD), acute kidney injury (AKI) or the like), heart disease(heart failure, pulmonary arterial hypertension or the like), centralnervous system disease (Parkinson's disease, Alzheimer's disease,cerebral stroke or the like), mitochondrial disease (Friedreich motorataxia, mitochondrial myopathy or the like), inflammatory disease (forexample, multiple sclerosis (MS), inflammatory bowel disease (IBD)),sickle cell disease, cancer and the like (Clin Sci (Lond). 2015 129(12):989-99; Non Patent Literature 3).

Bardoxolone methyl (CDDO-Me), which activates NRF2 by modifying a Cysresidue of KEAP1, exhibited the effect of improving kidney function in alarge scale clinical trial of CKD patients with type 2 diabetes;however, serious side effects, such as worsening of cardiovascular eventand onset of heart failure, were confirmed, and therefore, the clinicaltrial was stopped in an early stage (N Engl J Med. 2013 26; 369(26):2492-2503; Non Patent Literature 4). Low-molecular compounds inhibitingthe protein-protein interaction of NRF2-KEAP1 are expected to exhibiteffectiveness for the oxidative stress diseases described above byactivating NRF2 through a mechanism different from that of CDDO-Me.

Up until now, compounds of monocyclic type, two-ring-bound type andfused ring type that have an NRF2 regulating activity are known.

-   (1) The following compounds are known as the monocyclic type    compounds.

-   (2) The following compounds are known as the two-ring-bound type    compounds.

-   (3) The following compounds are known as the fused ring type    compounds.

-   (For symbols in the formulas, see the relevant publications.)

An object of the present invention is to provide a compound having anNRF2 activating activity, having a novel structure, and being expectedto be useful as a preventive or therapeutic agent for diseasesassociated with oxidative stress, in particular, hepatic disease (forexample, non-alcoholic steatohepatitis (NASH)), bile duct disease(primary sclerosing cholangitis (PSC) or the like), cardiovasculardisease (for example, heart failure or pulmonary arterial hypertension),lung disease (for example, chronic obstructive pulmonary disease(COPD)), kidney disease (for example, chronic kidney disease (CKD) oracute kidney injury (AKI)), central nervous system disease (for example,Parkinson's disease, Alzheimer's disease, cerebral stroke),mitochondrial disease (for example, Friedreich motor ataxia,mitochondrial myopathy), inflammatory disease (for example, multiplesclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease,cancer, or the like.

SUMMARY OF THE INVENTION

As a result of extensive studies in order to solve the problemsdescribed above, the present inventors have found that a macrocycliccompound represented by the following formula (I) has an NRF2 activatingactivity, and therefore, is expected to be useful as a preventive ortherapeutic agent for diseases associated with oxidative stress, inparticular, hepatic disease (for example, non-alcoholic steatohepatitis(NASH)), bile duct disease (primary sclerosing cholangitis (PSC) or thelike), cardiovascular disease (for example, heart failure or pulmonaryarterial hypertension), lung disease (for example, chronic obstructivepulmonary disease (COPD)), kidney disease (for example, chronic kidneydisease (CKD) or acute kidney injury (AKI)), central nervous systemdisease (for example, Parkinson's disease, Alzheimer's disease, cerebralstroke), mitochondrial disease (for example, Friedreich motor ataxia,mitochondrial myopathy), inflammatory disease (for example, multiplesclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease,cancer, or the like, thereby completing the present invention.

That is, the present invention is as follows:

<1>

A compound represented by the following formula (I):

-   wherein-   R¹ is OH, ORy or NHRy;-   Ry is an optionally substituted C₁₋₆ alkyl group or an optionally    substituted cyclic group;-   R² and R³, which may be the same or different, are a hydrogen atom    or an optionally substituted C₁₋₆ alkyl group, or R² and R³ are    joined together to form a C₃₋₆ cycloalkyl group;-   X is C(═O), SO₂ or CR^(x1)R^(x2);-   R^(x1) and R^(x2), which may be the same or different, are a    hydrogen atom or an optionally substituted C₁₋₆ alkyl group;-   ring A is a benzene ring which may have an additional    substituent(s);-   ring B is a benzene ring which may have an additional    substituent(s);-   ring C is an optionally substituted 5- or 6-membered aromatic ring    which may contain a heteroatom(s) in the ring; and-   L is optionally substituted, saturated or unsaturated linear C₄₋₈    alkylene optionally inserted by a heteroatom,-   or a salt thereof.    <2>

The compound according to <1> above or a salt thereof, wherein informula (I),

L is —(CR⁴R⁵)n—Y¹—(CR⁶R⁷)m—Y²—*

-   wherein * represents attachment to ring C;-   n is an integer of 2 or more and 4 or less;-   m is an integer of 1 or more and 4 or less;-   R⁴ and R⁵ are the same as or different from each other, and are each    a hydrogen atom, a halogen atom, OH, an optionally substituted C₁₋₆    alkyl group or an optionally substituted C₁₋₆ alkoxy group, or R⁴    and R⁵ are joined together to form an optionally substituted C₃₋₆    cycloalkyl group, and a plurality of R⁴ or a plurality of R⁵ may be    the same as or different from each other, and the adjacent R⁴ or R⁵    may be joined together to form a double bond;-   R⁶ and R⁷ are the same as or different from each other, and are each    a hydrogen atom, a halogen atom, OH, an optionally substituted C₁₋₆    alkyl group or an optionally substituted C₁₋₆ alkoxy group, or R⁶    and R⁷ are joined together to form an optionally substituted C₃₋₆    cycloalkyl group, and when m is 2 or more, a plurality of R⁶ or a    plurality of R⁷ may be the same as or different from each other, and    the adjacent R⁶ or R⁷ may be joined together to form a double bond;-   Y¹ and Y², which may be the same or different, are a bond, an oxygen    atom, a sulfur atom, SO, SO₂ or NR⁸, provided that when Y¹ is a    bond, m is 1 or 4; and-   R⁸ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group,    or an optionally substituted C₁₋₆ alkoxy group, provided that when a    plurality of R⁸ is present, the plurality of R⁸ may be the same as    or different from each other.    <3>

The compound according to <1> or <2> above, or a salt thereof, whereinin formula (I),

-   L is selected from the group consisting of the following formulas:

—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—*; and

—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—CR⁶R⁷—*.

<4-1>

The compound according to any one of <1> to <3> above, or a saltthereof, wherein in formula (I),

-   R¹ is OH or ORy;-   Ry is an optionally substituted cyclic group;-   R² and R³, which may be the same or different, are a hydrogen atom    or an optionally substituted C₁₋₆ alkyl group;-   X is C(═O);-   ring A is a benzene ring which may have an additional    substituent(s);-   ring B is a benzene ring which may have an additional    substituent(s); and-   ring C is an optionally substituted benzene ring.    <4-2>

The compound according to any of <1> to <3> above, or a salt thereof,wherein in formula (I),

-   R¹ is OH or ORy;-   Ry is a C₁₋₆ alkyl group;-   R² and R³, which may be the same or different, are a hydrogen atom    or a C₁₋₃ alkyl group;-   X is C(═O);-   ring A is a benzene ring which may have an additional substituent(s)    of a fluorine atom, a chlorine atom, a C₁₋₃ alkyl group optionally    substituted with 1 to 3 substituents (selected from a halogen atom    and a C₁₋₃ alkoxy group), or a C₁₋₃ alkoxy group optionally    substituted with 1 to 3 substituents (selected from a halogen atom    and a C₁₋₃ alkoxy group);-   ring B is a benzene ring which may have an additional substituent(s)    of a fluorine atom, a chlorine atom, a cyano group, a C₁₋₃ alkyl    group optionally substituted with 1 to 3 substituents (selected from    a halogen atom and a C₁₋₃ alkoxy group), or a C₁₋₃ alkoxy group    optionally substituted with 1 to 3 substituents (selected from a    halogen atom and a C₁₋₃ alkoxy group); and-   ring C is a group represented by the following formula:

-   wherein Z¹, Z², Z³, Z⁴ and Z⁵, which may be the same or different,    represent a carbon atom or a nitrogen atom;-   R^(c) represents a hydrogen atom, a halogen atom, a nitro group, a    cyano group, a hydroxy group, an optionally halogenated C₁₋₆ alkyl    group, an optionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀    cycloalkyl group; and-   R^(c1), R^(c2), R^(c3) and R^(c4), which may be the same or    different, are a hydrogen atom, a halogen atom, a nitro group, a    cyano group, a hydroxy group, an optionally halogenated C₁₋₆ alkyl    group, an optionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀    cycloalkyl group; or adjacent two of R^(c1), R^(c2), R^(c3) and    R^(c4) are joined together to form an optionally substituted ring,    provided that when Z¹, Z², Z³, Z⁴ or Z⁵ is a nitrogen atom, R^(c),    R^(c1), R^(c2), R^(c3) or R^(c4) is not present.    <5>

The compound according to any of <1> to <4> above, or a salt thereof,wherein in formula (I),

-   R¹ is OH;-   R² and R³, which may be the same or different, are a hydrogen atom    or a C₁₋₃ alkyl group;-   X is C(═O);-   ring A is a benzene ring which may have an additional substituent of    a C₁₋₃ alkyl group;-   ring B is a benzene ring which does not have an additional    substituent; and-   ring C is a group represented by the following formula:

-   wherein-   R^(c1) and R^(c4), which may be the same or different, are a    hydrogen atom, an optionally halogenated C₁₋₆ alkyl group, an    optionally halogenated C₁₋₆ alkoxy group, a chlorine atom, or a    fluorine atom, and R^(c2) and R^(c3) are each a hydrogen atom; and

L is —CH₂—CH₂—CH₂—CH₂—CH₂—*,

—CH₂—CH₂—CH₂—CH₂—O—*,

—CH₂—CH₂—CH₂—O—CH₂—*, or

—CH₂—CH₂—O—CH₂—CH₂—*.

<6>

The compound according to any of <1> to <5> above, or a salt thereof,wherein in formula (I),

-   R¹ is OH;-   R² and R³, which may be the same or different, are a hydrogen atom    or a methyl group;-   X is C(═O);-   ring A is a substructure represented by the following formula:

-   ring B is a benzene ring which does not have an additional    substituent;-   ring C is a group represented by the following formula:

-   wherein-   R^(c1) and R^(c4), which may be the same or different, are a    hydrogen atom, a chlorine atom, or a methyl group, and R^(c2) and    R^(c3) are each a hydrogen atom; and

L is —CH₂—CH₂—CH₂—CH2—CH₂—*,

—CH₂—CH₂—CH₂—CH₂—O—*,

—CH₂—CH₂—CH₂—O—CH₂—*, or

—CH₂—CH₂—O——CH₂—CH₂—*.

<7>

A compound selected from the group consisting of the following:

-   [32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetic    acid:

[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid:

2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]propionicacid:

2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propionicacid:

2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoicacid

-   or a salt thereof.    <7-2>

[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid:

-   or a salt thereof.    <7-3>

[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid:

-   or a salt thereof.    <8>

A medicament including the compound according to any of <1> to <7> aboveor a salt thereof.

-   <9>

The medicament according to <8> above, wherein the medicament is an NRF2activator.

<10>

The medicament according to <9> above, wherein the medicament is apreventive or therapeutic agent for hepatic and bile duct disease,cardiovascular disease, lung disease, kidney disease, central nervoussystem disease, cancer, sickle cell disease, mitochondrial disease, orinflammatory disease.

<11>

A pharmaceutical composition comprising the compound according to any of<1> to <7> above or a pharmaceutically acceptable salt thereof for usein prevention or treatment for hepatic and bile duct disease,cardiovascular disease, lung disease, kidney disease, central nervoussystem disease, cancer, sickle cell disease, mitochondrial disease, orinflammatory disease.

<12>

A method of activating NRF2 in a mammal comprising administering thecompound according to any of <1> to <7> above or a salt thereof to themammal in an effective amount.

<13>

A method of preventing or treating hepatic and bile duct disease,cardiovascular disease, lung disease, kidney disease, central nervoussystem disease, cancer, sickle cell disease, mitochondrial disease, orinflammatory disease in a mammal, comprising administering the compoundaccording to any of <1> to <7> or a salt thereof to the mammal.

<14>

Use of the compound according to any of <1> to <7> above or a saltthereof for producing a preventive or therapeutic agent for hepatic andbile duct disease, cardiovascular disease, lung disease, kidney disease,central nervous system disease, cancer, sickle cell disease,mitochondrial disease, or inflammatory disease.

The present invention can provide a compound that has an excellent NRF2activating activity, and is expected to be useful as a preventive ortherapeutic agent for diseases associated with oxidative stress, inparticular, hepatic and bile duct disease such as hepatic disease (forexample, non-alcoholic steatohepatitis (NASH)) and bile duct disease(primary sclerosing cholangitis (PSC) or the like), cardiovasculardisease (for example, heart failure or pulmonary arterial hypertension),lung disease (for example, chronic obstructive pulmonary disease(COPD)), kidney disease (for example, chronic kidney disease (CKD) oracute kidney injury (AKI)), central nervous system disease (for example,Parkinson's disease, Alzheimer's disease, cerebral stroke),mitochondrial disease (for example, Friedreich motor ataxia,mitochondrial myopathy), inflammatory disease (for example, multiplesclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease,cancer, or the like.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS (Detailed Descriptionof the Invention)

Hereinafter, the present invention will be described in detail.

Hereinafter, the definition of each substituent as used herein will bedescribed in detail. Unless noted otherwise, each substituent has thefollowing definition.

Examples of the “halogen atom” as used herein include fluorine,chlorine, bromine and iodine.

Examples of the “C₁₋₆ alkyl group” as used herein include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

Examples of the “cyclic group” in the “optionally substituted cyclicgroup” include a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, aC₆₋₁₄ aryl group, an aromatic heterocyclic group, and a non-aromaticheterocyclic group.

Note that the “optionally substituted ring” means a ring that does nothave a bonding hand of the cyclic group defined as the “optionallysubstituted cyclic group.”

Examples of the “C₃₋₁₀ cycloalkyl group” as used herein includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, and adamantyl.

The C₃₋₁₀ cycloalkyl group may be fused with a benzene ring, andexamples of such a fused ring include tetrahydronaphthyl anddihydroindenyl.

Examples of the “C₃₋₁₀ cycloalkenyl group” include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl.

Examples of the “C₆₋₁₄ aryl group” include phenyl, 1-naphthyl,2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

The C₆₋₁₄ aryl group described above may be fused with a C₃₋₁₀cycloalkane ring (preferably, a C₅₋₆ cycloalkane ring (for example,cyclopentane and cyclohexane)), and examples of such a fused ringinclude tetrahydronaphthyl and dihydroindenyl.

The aromatic heterocyclic group in the “cyclic group” of the “optionallysubstituted cyclic group” is preferably a 5- to 14-membered aromaticheterocyclic group, and more preferably a 5- to 6-membered monocyclicaromatic heterocyclic group (for example, pyridyl, thiazolyl, oxazolyl,pyrazolyl, triazolyl and thienyl), or a 8- to 14-membered fusedpolycyclic (preferably, bicyclic or tricyclic) aromatic heterocyclicgroup (for example, indazolyl, indolyl, benzimidazolyl, benzotriazolyl,benzothienyl and benzofuryl).

The non-aromatic heterocyclic group in the “cyclic group” of the“optionally substituted cyclic group” is preferably a 3- to 14-memberednon-aromatic heterocyclic group, and more preferably a 3- to 8-memberedmonocyclic non-aromatic heterocyclic group (for example, oxetanyl andtetrahydropyranyl) or a 9- to 14-membered fused polycyclic (preferably,bicyclic or tricyclic) non-aromatic heterocyclic group (for example,dihydrocumenyl, dihydrobenzofuryl, dihydrobenzodioxepinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolinyl,dihydrobenzodioxinyl, dihydrobenzoxazinyl and dihydrobenzoxazepinyl).

Furthermore, the non-aromatic heterocyclic group may be a spiro ring,and examples of such a spiro ring includespiro[1-benzofuran-2,1′-cyclopropane]-yl,spiro[1-benzofuran-2,1′-cyclohexane]-yl,tetrahydro-3H-spiro[1-benzofuran-2,4′-pyrane]-yl,spiro[1-benzofuran-2,1′-cyclopentane]yl, anddihydrospiro[1,4-benzoxazine-2,1′-cyclobutane]-yl.

Examples of the “C₃₋₆ cycloalkyl group” as used herein includecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of the “C₁₋₆ alkoxy group” as used herein include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy and hexyloxy.

Examples of the “5- or 6-membered aromatic ring which may contain aheteroatom(s) in the ring” as used herein include a 5- or 6-memberedaromatic heterocyclic ring containing, other than carbon atoms, 1 to 4heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom as the constituent atoms of the ring, or a 6-membered aromaticcarbocyclic ring not including heteroatoms.

In addition, the “optionally substituted 5- or 6-membered aromatic ringwhich may contain a heteroatom(s) in the ring” is specificallyrepresented by the following formulas:

-   wherein Z¹, Z², Z³, Z⁴ and Z⁵, which may be the same or different,    are a carbon atom or a nitrogen atom;-   R^(c) represents a hydrogen atom, or a halogen atom, a nitro group,    a cyano group, a hydroxy group, an optionally halogenated C₁₋₆ alkyl    group, an optionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀    cycloalkyl group; and-   R^(c1), R^(c2), R^(c3) and R^(c4), which may be the same or    different, are a hydrogen atom, or a halogen atom, a nitro group, a    cyano group, a hydroxy group, an optionally halogenated C₁₋₆ alkyl    group, an optionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀    cycloalkyl group; or adjacent two of R^(c1), R^(c2), R^(c3) and    R^(c4), taken together, may form an optionally substituted ring,    provided that when Z¹, Z², Z³, Z⁴ or Z⁵ is a nitrogen atom, R^(c),    R^(c1), R^(c2), R^(c3) and R^(c4) is not present.

Note that formulas (C-1) to (C-5) are attached to X and L in formula (I)at certain bonding positions.

“Optionally halogenated” as used herein means, for example, optionallysubstituted with 1 to 7, preferably 1 to 5 halogen atoms.

Suitable examples of such a 5- or 6-membered aromatic heterocyclic ringinclude thiophene, furan, pyrrole, imidazole, pyrazole, thiazole,isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine,pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, triazole, tetrazole, and triazine, and a 6-memberedaromatic carbocyclic ring not containing heteroatoms is a benzene ring.

The “saturated or unsaturated linear C₄₋₈ alkylene optionally insertedby a heteroatom” as used herein means a saturated or unsaturated linearalkylene group in which one or two heteroatoms selected from a nitrogenatom or NR^(c) (R^(c) is a hydrogen atom or a C₁₋₆ alkyl groupoptionally having a substituent), a sulfur atom, SO, SO₂, and an oxygenatom are inserted to an arbitrary position of a C₄₋₈ alkylene, therebydividing that alkylene into two or more; a saturated or unsaturatedlinear alkylene group that is substituted with a heteroatom describedabove; or a saturated or unsaturated linear C₄₋₈ alkylene group.

Further specifically, it is a group represented by the followingformula:

—(CR⁴R⁵)n—Y¹—(CR⁶R⁷)m—Y²—*

-   wherein * represents attachment to ring C;-   n is an integer of 2 or more and 4 or less;-   m is an integer of 1 or more and 4 or less;-   R⁴ and R⁵, which may be the same as or different from each other,    are a hydrogen atom, a halogen atom, OH, an optionally substituted    C₁₋₆ alkyl group or an optionally substituted C₁₋₆ alkoxy group, or    R⁴ and R⁵ are joined together to form an optionally substituted C₃₋₆    cycloalkyl group, and a plurality of R⁴ or a plurality of R⁵ may be    the same as or different from each other, and the adjacent R⁴ or R⁵    may be joined together to form a double bond;-   R⁶ and R⁷, which may be the same as or different from each other,    are each a hydrogen atom, a halogen atom, OH, an optionally    substituted C₁₋₆ alkyl group or an optionally substituted C₁₋₆    alkoxy group, or R⁶ and R⁷ are joined together to form an optionally    substituted C₃₋₆ cycloalkyl group, and when m is 2 or more, a    plurality of R⁶ or a plurality of R⁷ may be the same as or different    from each other, and the adjacent R⁶ or R⁷ may be joined together to    form a double bond;-   Y¹ and Y², which may be the same or different, are a bond, an oxygen    atom, NR⁸, a sulfur atom, SO or SO₂, provided that when Y¹ is a    bond, m is 1 or 4; and-   R⁸ is a hydrogen atom or an optionally substituted C₁₋₆ alkyl group,    provided that when a plurality of R⁸ is present, the plurality of R⁸    may be the same as or different from each other.

“R⁴ and R⁵ are joined together to form an optionally substituted C₃₋₆cycloalkyl group” or “R⁶ and R⁷ are joined together to form anoptionally substituted C₃₋₆ cycloalkyl group” means an optionallysubstituted C₃₋₆ cycloalkyl including the carbon atom to which R⁴ and R⁵are attached or the carbon atom to which R⁶ and R⁷ are attached as theconstituent element of the ring.

“the adjacent R⁶ or R⁷ may be joined together to form a double bond ”means, for example, in the case of —CR⁶R⁷—CR⁶R⁷—, being —CR⁶═CR⁷—,—CR⁷═CR⁶—, —CR⁷═CR⁷— or —CR⁶═CR⁶—.

Specifically, preferable groups represented by the formula:—(CR⁴R⁵)n—Y¹—(CR⁶R⁷)m—Y²—* wherein the symbols in the formula are asdefined above are the groups shown in Table 1 below.

TABLE 1 —CR4R5—CR4R5—CR4R5—CR6R7—* —CR4R5—CR4R5—CR4R5—O—CR6R7—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—* —CR4R5—CR4R5—CR4R5—CR4R5—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—* —CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—*—CR4R5—CR4R5—O—CR6R7—CR6R7—* —CR4R5—CR4R5—NR8—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—* —CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—*—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—* —CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—*—CR4R5—CR4R5—O—CR6R7—CR6R7—O—* —CR4R5—CR4R5—NR8—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—O—*—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—O—*—CP4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—O—*—CR4R5—CR4R5—O—CR6R7—CR6R7—NR8—* —CR4R5—CR4R5—NR8—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7NR8—*—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR4R5—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR4R5—O—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR4R5—NR8—CR6R7—CR6R7—CR6R7—CR6R7—NR8—*—CR4R5—CR4R5—CR4R5—CR6R7—O—* —CR4R5—CR4R5—CR4R5—CR4R5—CR6R7—O—*—CR4R5—CR4R5—CR4R5—CR6R7—NR8—* —CR4R5—CR4R5—CR4R5—CR4R5—CR6R7—NR8—*

Preferably, it is any of groups represented by the following formulas:

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—*; and

—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—CR⁶R⁷—*.

More preferably, it is any of groups represented by the followingformulas:

—CH₂—CH₂—CH₂—CH₂—CH₂—*; and

—CH₂—CH₂—CH₂—O—CH₂—*.

Examples of the substituent in the “optionally substituted C₁₋₆ alkylgroup”, the “optionally substituted cyclic group”, the “ a benzene ringwhich may have an additional substituent(s)”, the “optionallysubstituted 5- or 6-membered aromatic ring which may contain aheteroatom(s) in the ring”, and the “optionally substituted, saturatedor unsaturated linear C₄₋₈ alkylene optionally inserted by a heteroatom”as used herein include substituents selected from Substituent Group Adescribed below, and the number of the substituent is, for example, 1 to5 (preferably 1 to 3). When the number of the substituent is two ormore, those substituents may be the same as or different from eachother.

[Substituent Group A]

-   (1) Halogen atom;-   (2) Cyano group;-   (3) Nitro group;-   (4) Optionally substituted hydrocarbon group;-   (5) Optionally substituted heterocyclic group;-   (6) Acyl group;-   (7) Optionally substituted amino group;-   (8) Optionally substituted carbamoyl group;-   (9) Optionally substituted thiocarbamoyl group;-   (10) Optionally substituted sulfamoyl group;-   (11) Optionally substituted hydroxy group;-   (12) Optionally substituted sulfanyl (SH) group; and-   (13) Optionally substituted silyl group.

Examples of the “hydrocarbon group” of the “optionally substitutedhydrocarbon group” in Substituent Group A include a C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₁₀ cycloalkyl group, aC₃₋₁₀ cycloalkenyl group, a C₆₋₁₄ aryl group, and a C₇₋₁₆ aralkyl group.

Examples of the “C₂₋₆ alkenyl group” include ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl.

Examples of the “C₂₋₆ alkynyl group” include ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, and 4-methyl-2-pentynyl.

Examples of the “C₇₋₁₆ aralkyl group” include benzyl, phenethyl,naphthylmethyl, and phenylpropyl.

Examples of the “optionally substituted hydrocarbon group” inSubstituent Group A include a hydrocarbon group optionally having asubstituent selected from Substituent Group B described below.

[Substituent Group B]

-   (1) Halogen atom;-   (2) Nitro group;-   (3) Cyano group;-   (4) Oxo group;-   (5) Hydroxy group;-   (6) Optionally halogenated C₁₋₆ alkoxy group;-   (7) C₆₋₁₄ Aryloxy group (for example, phenoxy, naphthoxy);-   (8) C₇₋₁₆ Aralkyloxy group (for example, benzyloxy);-   (9) 5- to 14-Membered aromatic heterocyclic ring oxy group (for    example, pyridyloxy);-   (10) 3- to 14-Membered non-aromatic heterocyclic ring oxy group (for    example, morpholinyloxy, piperidinyloxy);-   (11) C₁₋₆ Alkyl-carbonyloxy group (for example, acetoxy,    propanoyloxy);-   (12) C₆₋₁₄ Aryl-carbonyloxy group (for example, benzoyloxy,    1-naphthoyloxy, 2-naphthoyloxy);-   (13) C₁₋₆Alkoxy-carbonyloxy group (for example, methoxycarbonyloxy,    ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy);-   (14) Mono- or di-C₁₋₆ alkyl-carbamoyloxy group (for example,    methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,    diethylcarbamoyloxy);-   (15) C₆₋₁₄ Aryl-carbamoyloxy group (phenylcarbamoyloxy,    naphthylcarbamoyloxy);-   (16) 5- to 14-Membered aromatic heterocyclic ring carbonyloxy group    (for example, nicotinoyloxy);-   (17) 3- to 14-Membered non-aromatic carbonyloxy group (for example,    morpholinylcarbonyloxy, piperidinylcarbonyloxy);-   (18) Optionally halogenated C₁₋₆ alkylsulfonyloxy group (for    example, methylsulfonyloxy, trifluoromethylsulfonyloxy);-   (19) C₆₋₁₄ Arylsulfonyloxy group optionally substituted with a C₁₋₆    alkyl group (for example, phenylsulfonyloxy, toluenesulfonyloxy);-   (20) Optionally halogenated C₁₋₆ alkylthio group;-   (21) 5- to 14-Membered aromatic heterocyclic group;-   (22) 3- to 14-Membered non-aromatic heterocyclic group;-   (23) Formyl group;-   (24) Carboxy group;-   (25) Optionally halogenated C₁₋₆ alkyl-carbonyl group;-   (26) C₆₋₁₄ Aryl-carbonyl group;-   (27) 5- to 14-Membered aromatic heterocyclic ring carbonyl group;-   (28) 3- to 14-Membered non-aromatic heterocyclic ring carbonyl    group;-   (29) C₁₋₆ Alkoxy-carbonyl group;-   (30) C₆₋₁₄ Aryloxy-carbonyl group (for example, phenyloxycarbonyl,    1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl);-   (31) C₇₋₁₆ Aralkyloxy-carbonyl group (for example,    benzyloxycarbonyl, phenethyloxycarbonyl);-   (32) Carbamoyl group;-   (33) Thiocarbamoyl group;-   (34) Mono-or di-C₁₋₆ alkyl-carbamoyl group;-   (35) C₆₋₁₄ Aryl-carbamoyl group (for example, phenylcarbamoyl);-   (36) 5- to 14-Membered aromatic heterocyclic ring carbamoyl group    (for example, pyridylcarbamoyl, thienylcarbamoyl);-   (37) 3- to 14-Membered non-aromatic heterocyclic ring carbamoyl    group (for example, morpholinylcarbamoyl, piperidinylcarbamoyl);-   (38) Optionally halogenated C₁₋₆ alkylsulfonyl group;-   (39) C₆₋₁₄ Arylsulfonyl group;-   (40) 5- to 14-Membered aromatic heterocyclic ring sulfonyl group    (for example, pyridylsulfonyl, thienylsulfonyl);-   (41) Optionally halogenated C₁₋₆ alkylsulfinyl group;-   (42) C₆₋₁₄ Arylsulfinyl group (for example, phenylsulfinyl,    1-naphthylsulfinyl, 2-naphthylsulfinyl);-   (43) 5- to 14-Membered aromatic heterocyclic ring sulfinyl group    (for example, pyridylsulfinyl, thienylsulfinyl);-   (44) Amino group;-   (45) Mono- or di-C₁₋₆ alkylamino group (for example, methylamino,    ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,    diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino);-   (46) Mono- or di-C₆₋₁₄ arylamino group (for example, phenylamino);-   (47) 5- to 14-Membered aromatic heterocyclic ring amino group (for    example, pyridylamino);-   (48) C₇₋₁₆ Aralkylamino group (for example, benzylamino);-   (49) Formylamino group;-   (50) C₁₋₆ Alkyl-carbonylamino group (for example, acetylamino,    propanoylamino, butanoylamino);-   (51) (C₁₋₆ Alkyl)(C₁₋₆ alkyl-carbonyl)amino group (for example,    N-acetyl-N-methylamino);-   (52) C₆₋₁₄ Aryl-carbonylamino group (for example,    phenylcarbonylamino, naphthylcarbonylamino);-   (53) C₁₋₆ Alkoxy-carbonylamino group (for example,    methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,    butoxycarbonylamino, tert-butoxycarbonylamino);-   (54) C₇₋₁₆ Aralkyloxy-carbonylamino group (for example,    benzyloxycarbonylamino);-   (55) C₁₋₆ Alkylsulfonylamino group (for example,    methylsulfonylamino, ethylsulfonylamino);-   (56) C₆₋₁₄ Arylsulfonylamino group optionally substituted with a    C₁₋₆ alkyl group (for example, phenylsulfonylamino,    toluenesulfonylamino);-   (57) Optionally halogenated C₁₋₆ alkyl group;-   (58) C₂₋₆ Alkenyl group;-   (59) C₂₋₆ Alkynyl group;-   (60) C₃₋₁₀ Cycloalkyl group;-   (61) C₃₋₁₀ Cycloalkenyl group; and-   (62) C₆₋₁₄ Aryl group.

The number of the substituent selected from Substituent B describedabove in the “optionally substituted hydrocarbon group” of SubstituentGroup A is, for example, 1 to 5, and preferably 1 to 3. When the numberof the substituent is two or more, those substituents may be the same asor different from each other.

Examples of the “heterocyclic group” in the “optionally substitutedheterocyclic group” of Substituent Group A include (i) an aromaticheterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a7- to 10-membered bridged heterocyclic group, all of which contain,other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogenatom, a sulfur atom and an oxygen atom as the constituent atoms of thering.

Examples of the “aromatic heterocyclic group” in the “heterocyclicgroup” of Substituent Group A (including the “5- to 14-membered aromaticheterocyclic group”) include a 5- to 14-membered (preferably, 5- to10-membered) aromatic heterocyclic group containing, other than carbonatoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atomand an oxygen atom as the constituent atoms of the ring.

Suitable examples of such an “aromatic heterocyclic group” include: a 5-to 6-membered monocyclic aromatic heterocyclic group such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; and a 8- to14-membered fused polycyclic (preferably, bicyclic or tricyclic)aromatic heterocyclic group such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolynyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,and phenoxazinyl.

Examples of the “non-aromatic heterocyclic group” in the “heterocyclicgroup” of Substituent Group A (including the “3- to 14-memberednon-aromatic heterocyclic group”) include a 3- to 14-membered(preferably, 4- to 10-membered) non-aromatic heterocyclic groupcontaining, other than carbon atoms, 1 to 4 heteroatoms selected from anitrogen atom, a sulfur atom and an oxygen atom as the constituent atomsof the ring.

Suitable examples of such a “non-aromatic heterocyclic group” include: a3- to 8-membered monocyclic non-aromatic heterocyclic group such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetarhydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; anda 9- to 14-membered fused polycyclic (preferably, bicyclic or tricyclic)non-aromatic heterocyclic group such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

Suitable examples of the “7- to 10-membered bridged heterocyclic group”in the “heterocyclic group” of Substituent Group A include quinuclidinyland 7-azabicyclo[2.2.1]heptanyl.

Examples of the “optionally substituted heterocyclic group” as usedherein include a heterocyclic group optionally having a substituentselected from Substituent Group B described above.

The number of the substituent in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituent is two or more, those substituents may be the same as ordifferent from each other.

Examples of the “optionally substituted amino group” of SubstituentGroup A include an amino group optionally having “1 or 2 substituentsselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ringcarbonyl group, a 3- to 14-membered non-aromatic heterocyclic ringcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to 14-memberedaromatic heterocyclic group, a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, aC₁₋₆ alkylsulfonyl group, and a C₆₋₁₄ arylsulfonyl group, all of whichoptionally have 1 to 3 substituents selected from Substituent Group A”.

Suitable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (for example, methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (for example, diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (for example, cyclopropylamino, cyclohexylamino),a mono- or di-C₆₋₁₄ arylamino group (for example, phenylamino), a mono-or di-C₇₋₁₆ aralkylamino group (for example, benzylamino,dibenzylamino), a mono- or di-(optionally halogenated C₁₋₆alkyl)-carbonylamino group (for example, acetylamino, propionylamino), amono- or di-C₆₋₁₄ aryl-carbonylamino group (for example, benzoylamino),a mono- or di-C₇₋₁₆ aralkyl-carbonylamino group (for example,benzylcarbonylamino), a mono- or di-5- to 14-membered aromaticheterocyclic ring carbonylamino group (for example, nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclic ring carbonylamino group (for example,piperidinylcarbonylamino), a mono- or di-C₁₋₆ alkoxy-carbonylamino group(for example, tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclic ring amino group (for example, pyridylamino), acarbamoylamino group, a (mono- or di-C₁₋₆ alkyl-carbamoyl)amino group(for example, methylcarbamoylamino), a (mono- or di-C₇₋₁₆aralkyl-carbamoyl)amino group (for example, benzylcarbamoylamino), aC₁₋₆ alkylsulfonylamino group (for example, mehtylsulfonylamino,ethylsulfonylamino), a C₆₋₁₄ arylsulfonylamino group (for example,phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group(for example, N-acetyl-N-methylamino), and a (C₁₋₆ alkyl)(C₆₋₁₄aryl-carbonyl)amino group (for example, N-benzoyl-N-methylamino).

Examples of the “optionally substituted carbamoyl group” of SubstituentGroup A include a carbamoyl group optionally having “1 or 2 substituentsselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ringcarbonyl group, a 3- to 14-membered non-aromatic heterocyclic ringcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to 14-memberedaromatic heterocyclic group, a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, and a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group,all of which optionally have 1 to 3 substituents selected fromSubstituent Group B”.

Suitable examples of the optionally substituted carbamoyl group includea carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, a mono- ordi-C₂₋₆ alkenyl-carbamoyl group (for example, diallylcarbamoyl), a mono-or di-C₃₋₁₀ cycloalkyl-carbamoyl group (for example,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (for example, phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (for example, acetylcarbamoyl, propionylcarbamoyl), a mono- ordi-C₆₋₁₄ aryl-carbonyl-carbamoyl group (for example, benzoylcarbamoyl),and a 5- to 14-membered aromatic heterocyclic ring carbamoyl group (forexample, pyridylcarbamoyl).

Examples of the “optionally substituted thiocarbamoyl group” ofSubstituent Group A include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ringcarbonyl group, a 3- to 14-membered non-aromatic heterocyclic ringcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to 14-memberedaromatic heterocyclic group, a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, and a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group,all of which optionally have 1 to 3 substituents selected fromSubstituent Group B”.

Suitable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (for example, methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (for example, diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (for example, cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(for example, phenylthiocarbamoyl), a mono- or di-C₇₋₁₆aralkyl-thiocarbamoyl group (for example, benzylthiocarbamoyl,phenethylthiocarbamoyl), a mono- or di-C₁₋₆ alkyl-carbonyl-thiocarbamoylgroup (for example, acetylthiocarbamoyl, propionylthiocarbamoyl), amono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoyl group (for example,benzoylthiocarbamoyl), and a 5- to 14-membered aromatic heterocyclicring carbamoyl group (for example, pyridylthiocarbamoyl).

Examples of the “optionally substituted sulfamoyl group” of SubstituentGroup A include a sulfamoyl group optionally having “1 or 2 substituentsselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ringcarbonyl group, a 3- to 14-membered non-aromatic heterocyclic ringcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to 14-memberedaromatic heterocyclic group, a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, and a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group,all of which optionally have 1 to 3 substituents selected fromSubstituent Group B”.

Suitable examples of the optionally substituted sulfamoyl group includea sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group (forexample, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (for example, diallylsulfamoyl), a mono- ordi-C₃₋₁₀ cycloalkyl-sulfamoyl group (for example, cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (forexample, phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group(for example, benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (for example, acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(for example, benzoylsulfamoyl), and a 5- to 14-membered aromaticheterocyclic ring sulfamoyl group (for example, pyridylsulfamoyl).

Examples of the “optionally substituted hydroxy group” of SubstituentGroup A include a hydroxy group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ringcarbonyl group, a 3- to 14-membered non-aromatic heterocyclic ringcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to 14-memberedaromatic heterocyclic group, a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, aC₁₋₆ alkylsulfonyl group, and a C₆₋₁₄ arylsulfonyl group, all of whichoptionally have 1 to 3 substituents selected from Substituent Group B”.

Suitable examples of the optionally substituted hydroxy group include ahydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (forexample, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (for example, cyclohexyloxy), a C₆₋₁₄ aryloxy group(for example, phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (forexample, benzyloxy, phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (forexample, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,pivaloyloxy), a C₆₋₁₄ aryl-carbonyloxy group (for example, benzoyloxy),a C₇₋₁₆ aralkyl-carbonyloxy group (for example, benzylcarbonyloxy), a 5-to 14-membered aromatic heterocyclic ring carbonyloxy group (forexample, nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclicring carbonyloxy group (for example, piperidinylcarbonyloxy), a C₁₋₆alkoxy-carbonyloxy group (for example, tert-butoxycarbonyloxy), a 5- to14-membered aromatic heterocyclic ring oxy group (for example,pyridyloxy), a carbamoyloxy group, a C₁₋₆ alkyl-carbamoyloxy group (forexample, methylcarbamoyloxy), a C₇₋₁₆ aralkyl-carbamoyloxy group (forexample, benzylcarbamoyloxy), a C₁₋₆ alkylsulfonyloxy group (forexample, mehtylsulfonyloxy, ethylsulfonyloxy), and a C₆₋₁₄arylsulfonyloxy group (for example, phenylsulfonyloxy).

Examples of the “optionally substituted sulfanyl group” of SubstituentGroup A include a sulfanyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, and a 5- to14-membered aromatic heterocyclic group, all of which optionally have 1to 3 substituents selected from Substituent Group B”, and a halogenatedsulfanyl group.

Suitable examples of the optionally substituted sulfanyl group include asulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(for example, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio),a C₃₋₁₀ cycloalkylthio group (for example, cyclohexylthio), a C₆₋₁₄arylthio group (for example, phenylthio, naphthylthio), a C₇₋₁₆aralkylthio group (for example, benzylthio, phenethylthio), a C₁₋₆alkyl-carbonylthio group (for example, acetylthio, propionylthio,butyrylthio, isobutyrylthio, pivaloylthio), a C₆₋₁₄ aryl-carbonylthiogroup (for example, benzoylthio), a 5- to 14-membered aromaticheterocyclic ring thio group (for example, pyridylthio), and ahalogenated thio group (for example, pentafluorothio).

Examples of the “C₃₋₁₀ cycloalkyloxy group” as used herein includecyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxy, and cyclooctyloxy.

Examples of the “C₁₋₆ alkylthio group” as used herein includemethylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

Examples of the “optionally substituted silyl group” of SubstituentGroup A include a silyl group optionally having “1 to 3 substituentsselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, and a C₇₋₁₆ aralkyl group, all ofwhich optionally have 1 to 3 substituents selected from SubstituentGroup B”.

Suitable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (for example, trimethylsilyl,tert-butyl(dimethyl)silyl).

Hereinafter, the definition of each symbol in formula (I) will bedescribed in detail.

R¹ is preferably OH or ORy.

Ry is preferably a C₁₋₆ alkyl group.

R¹ is more preferably OH.

R² and R³ are preferably the same or different, and are each a hydrogenatom or an optionally substituted C₁₋₆ alkyl group (for example,methyl).

R² and R³ are more preferably the same or different, and are each ahydrogen atom or a C₁₋₃ alkyl group (for example, methyl).

Particularly preferably, R² and R³ are each a hydrogen atom or a methylgroup.

X is preferably C(═O).

The “benzene ring” of the “a benzene ring which may have an additionalsubstituent(s)” indicated as ring A may be further substituted with, forexample, a substituent(s) selected from Substituent Group A describedabove, and the number of the substituent is, for example, 1 to 3. Whenthe number of the substituent is two or more, those substituents may bethe same as or different from each other.

Here, when the benzene ring of ring A has an additional substituent(s),that position of substitution preferably includes a position selectedfrom positions a and b indicated by the following arrows:

-   wherein the symbols in the formula are as defined above.

Ring A is preferably a benzene ring which may have an additionalsubstituent(s) of a fluorine atom, a chlorine atom, a C₁₋₃ alkyl groupoptionally substituted with 1 to 3 substituents (selected from a halogenatom and a C₁₋₃ alkoxy group), or a C₁₋₃ alkoxy group optionallysubstituted with 1 to 3 substituents (selected from a halogen atom and aC₁₋₃ alkoxy group).

Further preferably, ring A is a benzene ring which may have anadditional substituent(s) of 1 to 3 substituents selected from:

(a) a C₁₋₆ alkyl group (for example, methyl); and

(b) a C₁₋₆ alkoxy group (for example, methoxy).

More preferably, ring A is a benzene ring which has an additionalsubstituent(s) of one substituent selected from:

(a) a C₁₋₃ alkyl group (for example, methyl); and

(b) a C₁₋₃ alkoxy group (for example, methoxy).

Here, the position of substitution on the benzene ring of ring A ispreferably a position a or b indicated by the following arrows:

-   wherein the symbols in the formula are as defined above.

In another embodiment, ring A is more preferably a benzene ring whichhas an additional substituent(s) of 1 or 2 substituents selected from:

(a) a C₁₋₃ alkyl group (for example, methyl); and

(b) a C₁₋₃ alkoxy group (for example, methoxy).

Here, the position(s) of substitution on the benzene ring of ring A ispreferably a position selected from positions a and b indicated by thefollowing arrows:

-   wherein the symbols in the formula are as defined above.

In such an embodiment, ring A is further preferably a benzene ring whichhas an additional substituent of a C₁₋₃ alkyl group (for example,methyl).

Here, the position of substitution on the benzene ring of ring A ispreferably position a indicated by the following arrow:

-   wherein the symbols in the formula are as defined above.

A substructure represented by the following formula:

-   wherein the symbols in the formula are as defined above, is    preferably a substructure represented by the following formula:

-   wherein-   R^(a) represents a hydrogen atom or a C₁₋₆ alkyl group;-   R^(b) represents a hydrogen atom or a C₁₋₆ alkoxy group; and-   L has the same meaning as described above.

Here, R^(a) is preferably a C₁₋₃ alkyl group (for example, methyl), andmore preferably methyl. R^(b) is preferably a hydrogen atom or a C₁₋₃alkoxy group (for example, methoxy).

Further preferably, ring A is a substructure represented by thefollowing formula:

The “benzene ring” of the “a benzene ring which may have an additionalsubstituent(s)” indicated as ring B may have an additionalsubstituent(s), for example, a substituent selected from SubstituentGroup A described above, and the number of the substituent is, forexample, 1 to 3. When the number of the substituent is two or more,those substituents may be the same as or different from each other.

Ring B is preferably a benzene ring which may have an additionalsubstituent(s) of a fluorine atom, a chlorine atom, a cyano group, aC₁₋₃ alkyl group optionally substituted with 1 to 3 substituents(selected from a halogen atom and a C₁₋₃ alkoxy group), or a C₁₋₃ alkoxygroup optionally substituted with 1 to 3 substituents (selected from ahalogen atom and a C₁₋₃ alkoxy group).

Ring B is more preferably a benzene ring which does not have anadditional substituent. Here, “which does not have an additionalsubstituent” indicates that ring B is the same as ring B described informula I and does not have a substituent other than the substituents onring B described in formula I.

The “optionally substituted 5- or 6-membered aromatic ring which maycontain a heteroatom(s) in the ring” indicated as ring C is preferably aring represented by the following formula:

-   wherein Z¹, Z², Z³, Z⁴ and Z⁵, which may be the same or different,    are a carbon atom or a nitrogen atom;-   R^(c) represents H, a halogen atom, a nitro group, a cyano group, a    hydroxy group, an optionally halogenated C₁₋₆ alkyl group, an    optionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀ cycloalkyl    group; and-   R^(c1), R^(c2), R^(c3) and R^(c4), which may be the same or    different, are H, a halogen atom, a nitro group, a cyano group, a    hydroxy group, an optionally halogenated C₁₋₆ alkyl group, an    optionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀ cycloalkyl    group; or adjacent two of R^(c1), R^(c2), R^(c3) and R^(c4) may be    joined together to form an optionally substituted ring, provided    that when Z¹, Z², Z³, Z⁴ or Z⁵ is a nitrogen atom, R^(c), R^(c1),    R^(c2), R^(c3) and R^(c4) is not present.

In addition, formulas (C-1) to (C-5) are attached to X and L in formula(I) at certain bonding positions.

Preferably, ring C is any of groups represented by the followingformulas:

-   wherein Z¹, Z², Z³, Z⁴ and Z⁵, which may be the same or different,    are a carbon atom or a nitrogen atom.

Further preferably, ring C is a group wherein Z¹, Z², Z³, Z⁴ and Z⁵ areeach a carbon atom; and R^(c1), R^(c2), R^(c3) and R^(c4), which may bethe same or different, are H, or a halogen atom, a nitro group, a cyanogroup, a hydroxy group, an optionally halogenated C₁₋₆ alkyl group, anoptionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀ cycloalkyl group;or adjacent two of R^(c1), R^(c2), R^(c3) and R^(c4) may be joinedtogether to form an optionally substituted ring,

Further preferably, ring C is a ring represented by formula (C-5), andis a group wherein adjacent two of R^(c1), R^(c2), R^(c3) and R^(c4) maybe joined together to form an optionally substituted saturated ring.

The “saturated ring” of the “optionally substituted saturated ring”means a C₅₋₈ cycloalkyl ring or a saturated heterocyclic ring, and sucha saturated heterocyclic ring means a 5- or 8-membered saturatedheterocyclic ring containing, other than carbon atoms, 1 to 4heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom as the constituent atoms of the ring. Preferable examples thereofinclude a 5- to 6-membered saturated heterocyclic ring (for example,tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, morpholine). Morepreferably, it is optionally substituted tetrahydropyran or optionallysubstituted morpholine.

The substituent in the “optionally substituted saturated ring” means 1to 3 substituents that may be the same or different, and are selectedfrom a halogen atom, a nitro group, a cyano group, a hydroxy group, anoxo group, an optionally halogenated C₁₋₆ alkyl group, an optionallyhalogenated C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, and a C₃₋₁₀cycloalkyl-C₁₋₆ alkyl group.

More preferably, ring C is a ring represented by formula (C-5), whereinall of Z¹, Z², Z⁴ and Z⁵ are carbon atoms; and in one of combinations,R^(c1) and R^(c2) or R^(c3) and R^(c4), the two groups may be the sameor different, and are H, or a halogen atom, a nitro group, a cyanogroup, a hydroxy group, an optionally halogenated C₁₋₆ alkyl group, anoptionally halogenated C₁₋₆ alkoxy group, or a C₃₋₁₀ cycloalkyl group;and in the other combination, adjacent two of R^(c1), R^(c2), R^(c3) andR^(c4) are joined together to form a 5- or 6-membered heterocyclic ringcontaining, other than carbon atoms, 1 to 4 heteroatoms selected from anitrogen atom, a sulfur atom and an oxygen atom as the constituent atomsof the ring.

The heterocyclic ring described above may be an aromatic heterocyclicring or a non-aromatic heterocyclic ring. Examples of the aromaticheterocyclic ring include, among those described as the monocyclicaromatic heterocyclic ring mentioned above, for example, pyridyl,thiazolyl, oxazolyl, pyrazolyl, triazolyl, and thienyl. Examples of thenon-aromatic heterocyclic ring include, among the monocyclicnon-aromatic heterocyclic ring mentioned above, those that are 5- or6-membered, such as tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl,pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl,pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl,tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl,piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl,dihydrothiopyranyl, tetrahydropyrimidinyl, and tetrahydropyridazinyl.Preferably, it is tetrahydrofuran or morpholine.

When the ring described above is substituted, it may be substituted with1 to 3 substituents that may be the same or different, and are selectedfrom a halogen atom, a nitro group, a cyano group, a hydroxy group, anoxo group, an optionally halogenated C₁₋₆ alkyl group, an optionallyhalogenated C₁₋₆ alkoxy group, a C₃₋₁₀ cycloalkyl group, and a C₃₋₁₀cycloalkyl-C₁₋₆ alkyl group.

More specifically, ring C is preferably a group represented by thefollowing formula:

-   wherein-   R^(c1) and R^(c4), which may be the same or different, are a    hydrogen atom, an optionally halogenated C₁₋₆ alkyl group, a    chlorine atom, an optionally halogenated C₁₋₆ alkoxy group, or a    fluorine atom, and R^(c2) and R^(c3) are each a hydrogen atom.

Further specifically, ring C is preferably a group represented by thefollowing formula:

-   wherein-   R^(c1) and R^(c4), which may be the same or different, are a    hydrogen atom, a methyl group, or a chlorine atom, and R^(c2) and    R^(c3) are each a hydrogen atom.

L is preferably —(CR⁴R⁵)n—Y¹—(CR⁶R⁷)m—Y²—*

-   wherein * represents attachment to ring C;-   n is an integer of 2 or more and 4 or less;-   m is an integer of 1 or more and 4 or less;-   R⁴ and R⁵, which may be the same as or different from each other,    are each a hydrogen atom, a halogen atom, OH, an optionally    substituted C₁₋₆ alkyl group or an optionally substituted C₁₋₆    alkoxy group, or R⁴ and R⁵ are joined together to form an optionally    substituted C₃₋₆ cycloalkyl group, and a plurality of R⁴ or a    plurality of R⁵ may be the same as or different from each other, and    the adjacent R⁴ or R⁵ may be joined together to form a double bond;-   R⁶ and R⁷, which may be the same as or different from each other,    are each a hydrogen atom, a halogen atom, OH, an optionally    substituted C₁₋₆ alkyl group or an optionally substituted C₁₋₆    alkoxy group, or R⁶ and R⁷ are joined together to form an optionally    substituted C₃₋₆ cycloalkyl group, and when m is 2 or more, a    plurality of R⁶ or a plurality of R⁷ may be the same as or different    from each other, and the adjacent R⁶ or R⁷ may be joined together to    form a double bond;-   Y¹ and Y², which may be the same or different, are a bond, an oxygen    atom or NR⁸, provided that when Y¹ is a bond, m is 1 or 4; and-   R⁸ is a hydrogen atom or an optionally substituted C₁₋₆ alkyl group.

Further preferably, L is any of groups represented by the followingformulas:

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O —*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O —CR⁶R⁷—*; and

—CR⁴R⁵—CR⁴R⁵—O —CR⁶R⁷—CR⁶R⁷—*.

Most preferably, L is

—CH₂—CH₂—CH₂—CH₂—CH₂—*, or

—CH₂—CH₂—CH₂—O —CH₂—*.

Examples of the compound represented by formula (I) (hereinafter, alsoreferred to as compound (I)) include the following Compounds A to D, ora salt thereof.

[Compound A]

-   A compound or a salt thereof, in which:-   R¹ is OH;-   R² and R³, which may be the same or different, are a hydrogen atom    or an optionally substituted C₁₋₆ alkyl group;-   X is C(═O);

ring A is a benzene ring which may have an additional substituent(s);

ring B is a benzene ring which may have an additional substituent(s);

ring C is an optionally substituted benzene ring; and

L is —CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—*; or

—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—CR⁶R⁷—*.

[Compound B]

-   A compound or a salt thereof, in which:-   R¹ is NHRy;-   Ry is an optionally substituted cyclic group;-   R² and R³, which may be the same or different, are a hydrogen atom    or an optionally substituted C₁₋₆ alkyl group;-   X is C(═O);-   ring A is a benzene ring which may have an additional    substituent(s);-   ring B is a benzene ring which may have an additional    substituent(s);-   ring C is an optionally substituted benzene ring; and

L is —CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—*; or

—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—CR⁶R⁷—*.

[Compound C]

-   A compound or a salt thereof, in which:-   R¹ is OH;-   R² and R³, which may be the same or different, are a hydrogen atom    or an optionally substituted C₁₋₆ alkyl group;-   X is C(═O);-   ring A is a benzene ring which may have an additional    substituent(s);-   ring B is a benzene ring which may have an additional    substituent(s);-   ring C is a group represented by the following formula:

-   wherein all of Z¹, Z², Z⁴ and Z⁵ are carbon atoms; and in one of    combinations, R^(c1) and R^(c2) or R^(c3) and R^(c4), the two groups    which may be the same or different, are a hydrogen atom, or a    halogen atom, a nitro group, a cyano group, a hydroxy group, an    optionally halogenated C₁₋₆ alkyl group, an optionally halogenated    C₁₋₆ alkoxy group, or a C₃₋₁₀ cycloalkyl group; and in the other    combination, adjacent two of R^(c1), R^(c2), R^(c3) and R^(c4) are    joined together to form an optionally substituted ring; and

L is —CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—*; or

—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—CR⁶R⁷—*.

[Compound D]

-   A compound or a salt thereof, in which:-   R¹ is ORy;-   Ry is an optionally substituted C₁₋₆ alkyl group;-   R² and R³, which may be the same or different, are a hydrogen atom    or an optionally substituted C₁₋₆ alkyl group;-   X is C(═O);-   ring A is a benzene ring which may have an additional    substituent(s);-   ring B is a benzene ring which may have an additional    substituent(s);-   ring C is an optionally substituted benzene ring; and

L is —CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O—*;

—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O —CR⁶R⁷—*; or

—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—CR⁶R⁷—*.

Preferably, compound (I) is Compound A or a salt thereof.

Specific examples of compound (I) include compounds of Examples 1 to 68and salts thereof.

When compound (I) is a salt, examples of such a salt include metalsalts, ammonium salt, salts with organic bases, salts with inorganicacids, salts with organic acids, and salts with basic or acidic aminoacids. Suitable examples of the metal salt include alkali metal saltssuch as sodium salt and potassium salt; alkaline earth metal salts suchas calcium salt, magnesium salt and barium salt; and aluminum salt.Suitable examples of the salt with an organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, andN,N′-dibenzylethylenediamine. Suitable examples of the metal with aninorganic acid include salts with hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, and phosphoric acid. Suitable examples ofthe salt with an organic acid include salts with formic acid, aceticacid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.Suitable examples of the salt with a basic amino acid include salts witharginine, lysine and ornithine, and suitable examples of the salt withan acidic amino acid include salts with aspartic acid and glutamic acid.Among them, preferable are pharmaceutically acceptable salts. Forexample, when an acidic functional group is included in the compound,examples thereof include inorganic salts such as alkali metal salts (forexample, sodium salt, potassium salt) and alkaline earth metal salts(for example, calcium salt, magnesium salt, barium salt), ammonium saltand the like, and when a basic functional group is included in thecompound, examples thereof include salts with inorganic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid andphosphoric acid, or salts with organic acids such as acetic acid,phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonicacid.

When compound (I) has isomers such as tautomers, enantiomers,stereoisomers, regioisomers and rotamers, either one of isomers and amixture thereof are both encompassed in the inventive compound.Furthermore, when compound (I) has enantiomers, an enantiomer resolvedfrom the racemate is also encompassed in compound (I).

Compound (I) may be a crystal, and whether it has only one crystal formor a mixture of crystal forms, it is encompassed in compound (I).

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystalline materialcomposed of two or more unique solids at room temperature, each solidhaving different physical properties (for example, structure, meltingpoint, heat of fusion, hygroscopicity, solubility and stability). Thecocrystal or cocrystal salt can be produced by cocrystallization methodsknown per se.

Compound (I) may be a solvate (for example, hydrate) or a non-solvate(for example, non-hydrate), and either is encompassed in compound (I).

Further, deuterated products obtained by replacing ¹H with ²H(D) is alsoencompassed in compound (I).

Compounds labeled or substituted with an isotope (for example, ³H, ¹¹C,¹⁴C, ¹⁸F, ³⁵S, ¹²⁵I) or the like are also encompassed in compound (I).For example, compounds labeled or substituted with an isotope can beused as a tracer for use in positron emission tomography (PET) (PETtracer), and can be useful in fields such as medical diagnosis.

Hereinafter, a method of producing the inventive compound will bedescribed.

Ingredients and reagents used in each step of the following productionmethod, and obtained compounds may be in their salt forms. Examples ofsuch salts include salts or the like that are the same as salts of theinventive compound mentioned above.

When a compound obtained in each step is a free compound, it can betransformed into a salt of interest by a method known per se. On theother hand, when a compound obtained in each step is a salt, it can betransformed into a free form or another salt of interest by a methodknown per se.

A compound obtained in each step can remain a reaction solution or beused for next reaction after being obtained as a crude product.Alternatively, a compound obtained in each step can be, in accordancewith a normal method, isolated and/or purified from a reaction mixtureby separating means such as concentration, crystallization,distillation, solvent extraction, fractional distillation, andchromatography. A racemic compound can be separated into chiralcompounds using a chiral column for purification.

When ingredients and reagent compounds for each step are commerciallyavailable, commercial products can be used as they are.

In reaction of each step, reaction time may be different depending onreagents and solvents to be used, but it is normally 1 minute to 7 days,and preferably 10 minutes to 8 hours if there is no particulardescription.

In reaction of each step, reaction temperature may be differentdepending on reagents and solvents to be used, but it is normally −78°C. to 300° C., and preferably −78° C. to 150° C. if there is noparticular description.

In reaction of each step, pressure may be different depending onreagents and solvents to be used, but it is normally 1 atm to 20 atm,and preferably 1 atm to 3 atm if there is no particular description.

In reaction of each step, for example, a microwave synthesis apparatusmay be used such as Initiator manufactured by Biotage. Reactiontemperature may be different depending on reagents and solvents to beused, but it is normally room temperature to 300° C., and preferably 50°C. to 250° C. if there is no particular description. Reaction time maybe different depending on reagents and solvents to be used, but it isnormally 1 minute to 48 hours, and preferably 1 minute to 8 hours ifthere is no particular description.

In reaction of each step, a reagent is used in an amount of 0.5equivalent to 20 equivalent, and preferably 0.8 equivalent to 5equivalent relative to a substrate if there is no particulardescription. When a reagent is used as a catalyst, the reagent is usedin an amount of 0.001 equivalent to 1 equivalent, and preferably 0.01equivalent to 0.2 equivalent relative to a substrate. When a reagentalso acts as a reaction solvent, the reagent is used in a solventamount.

In reaction of each step, that reaction is carried out with no solvent,or in a dissolved or suspended state in an appropriate solvent if thereis no particular description. Specific examples of the solvent includesolvents described in Examples, or the following:

-   alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol    and the like; ethers: diethyl ether, diphenyl ether,    tetrahydrofuran, 1,2-dimethoxyethane and the like, cyclopentyl    methyl ether;-   aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;-   saturated hydrocarbons: cyclohexane, hexane and the like;-   amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;-   halogenated hydrocarbons: dichloromethane, dichloroethane, carbon    tetrachloride and the like;-   nitriles: acetonitrile and the like;-   sulfoxides: dimethylsulfoxide and the like;-   aromatic organic bases: pyridine and the like;-   acid anhydrides: acetic anhydride and the like;-   organic acids: formic acid, acetic acid, trifluoroacetic acid and    the like;-   inorganic acids: hydrochloric acid, sulfuric acid and the like;-   esters: ethyl acetate and the like;-   ketones: acetone, methyl ethyl ketone and the like; and-   water.

Two or more of the solvents described above may be mixed in anappropriate proportion for use.

When a base is used in reaction of each step, for example, bases shownbelow or bases described in Examples are used:

-   inorganic bases: sodium hydroxide, potassium phosphate, sodium    phosphate, potassium hydroxide, magnesium hydroxide, sodium    carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate    and the like;-   organic bases: triethylamine, diethylamine, pyridine,    4-dimethylaminopyridine, N,N-dimethylaniline,    1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,    imidazole, piperidine, potassium trimethylsilanolate and the like;-   metal alkoxides; sodium ethoxide, potassium tert-butoxide and the    like;-   alkali metal hydrides: sodium hydride and the like;-   metal amides: sodium amide, lithium diisopropylamide, lithium    hexamethyldisilazide and the like; and-   organic lithiums: n-butyllithium and the like.

When an acid or an acidic catalyst is used in reaction of each step, forexample, acids or acidic catalysts shown below, or acids or acidiccatalysts described in Examples are used:

-   inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,    hydrobromic acid, phosphoric acid and the like;-   organic acids: acetic acid, trifluoroacetic acid, citric acid,    p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; and-   Lewis acids: boron trifluoride-diethyl ether complex, zinc iodide,    anhydrous aluminum chloride, anhydrous zinc chloride, titanium    chloride, anhydrous iron chloride and the like.

Reaction of each step is carried out in accordance with a method knownper se, for example, methods described in The Fifth Series ofExperimental Chemistry, vol. 13 to 19 (edited by The Chemical Society ofJapan); The New Experimental Chemistry, vol. 14 to 15 (edited by TheChemical Society of Japan); Fine Organic Chemistry, Revised 2nd Edition(L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions; TheReaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha);ORGANIC SYNTHESES Collective Volume I to VII (John Wiley & Sons Inc.);Modern Organic Synthesis in the Laboratory A Collection of StandardExperimental Procedures (written by Jie Jack Li, published by. OXFORDUNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14(Elsevier, Inc.); Strategic Applications of Named Reactions in OrganicSynthesis (translated by Kiyoshi Tomioka, issued by Kagakudojin);Comprehensive Organic Transformations (VCH Publishers Inc.), issued in1989; and the like, or methods described in Examples.

When hydrolysis reaction is carried out in each step, an acid or a baseis used as a reagent. In addition, when acid hydrolysis reaction for atert-butyl ester is carried out, formic acid, triethylsilane or the likemay be added in order to reductively trap a secondarily producedtert-butyl cation.

When esterification reaction, amidation reaction, or ureation reactionis carried out in each step, examples of the reagent to be used includeacyl halide forms such as acid chlorides and acid bromides; andactivated carboxylic acids in the form of acid anhydride, active ester,sulfuric ester or the like. Examples of the activator for a carboxylicacid include carbodiimide-based condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD);triazine-based condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM); carbonate ester-based condensing agentssuch as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU);1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxidetetrafluoroborate (TBTU); sulfuric acid; and a combination thereof. Whena carbodiimide-based condensing agent is used, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu) anddimethylaminopyridine (DMAP) may be further added to the reaction.

When alkylation reaction is carried out in each step, used are anelectrophile such as a halogenated alkyl or an optionally substitutedsulfonyloxy group (for example, methanesulfonyloxy, ethanesulfonyloxy,trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxyand the like), and a nucleophile (for example, amine, alcohol, activemethylene compound adjacent to an electroattracting group and the like)and a base (for example, organic base, metal alkoxide, inorganic baseand the like) as reagents. In addition, the alkylation can also becarried out, after transforming an alcohol into an active ester, in thepresence of a silyl enol ether and an acid such as1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide.Moreover, the alkylation can also be carried out in the presence of analcohol, a silyl enol ether and a Lewis acid.

In each step, protection or deprotection reaction of a functional groupis carried out in accordance with a method known per se, for example,methods described in “Protective Groups in Organic Synthesis, 4th Ed.”(written by Theodora W. Greene, Peter G. M. Wuts), Wiley-Interscience,issued in 2007; “Protecting Groups 3rd Ed.” (written by P. J.Kocienski), Thieme, issued in 2004; and the like, or methods describedin Examples.

Examples of the protecting group of a hydroxy group of alcohol and thelike and a phenolic hydroxy group include ether protecting groups suchas methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether andtetrahydropyranyl ether; carboxylate ester protecting groups such asacetate ester; sulfonate ester protecting groups such asmethanesulfonate ester; and carbonate ester protecting groups such astert-butylcarbonate.

Examples of the protecting group of a carbonyl group of aldehyde includeacetal protecting groups such as dimethyl acetal; and cyclic acetalprotecting groups such as 1,3-dioxane.

Examples of the protecting group of a carbonyl group of ketone includeketal protecting groups such as dimethyl ketal; cyclic ketal protectinggroups such as 1,3-dioxane; oxime protecting groups such asO-methyloxime; and hydrazone protecting groups such asN,N-dimethylhydrazone.

Examples of the protecting group of a carboxyl group include esterprotecting groups such as methyl ester; and amide protecting groups suchas N,N-dimethylamide.

Examples of the protecting group of thiol include ether protectinggroups such as benzyl thioether; and ester protecting groups such asthioacetate ester, thiocarbonate and thiocarbamate.

Examples of the protecting group of an amino group and an aromaticheterocycle such as imidazole, pyrrole and indole include carbamateprotecting groups such as benzyl carbamate and tert-butylcarbamate;amide protecting groups such as acetamide; alkylamine protecting groupssuch as N-triphenylmethylamine; and sulfonamide protecting groups suchas methanesulfonamide.

The protecting group can be removed by a method known per se, forexample, a method using acid, base, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate or trialkylsilyl halide (for example,trimethylsilyl iodide, trimethylsilyl bromide), a reduction method, andthe like. Upon transforming an alkyl ester compound into a carboxylicacid compound, the transformation can be carried out using a strong base(potassium trimethylsilanolate), hydrogen-palladium catalyst, orzerovalent palladium catalyst.

When coupling reaction is carried out in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0) and1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride; nickelcompounds such as tetrakis(triphenylphosphine)nickel(0); rhodiumcompounds such as chloro(1,5-cyclooctadiene)rhodium(I) (dimer) andtris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; coppercompounds such as copper oxide and copper(I) iodide; and platinumcompounds. In addition, a phosphine ligand may be added to the reaction,and examples of such a phosphine include triphenylphosphine,1,1′-bis(diphenylphosphino)ferrocene, and tri-o-tolylphosphine. Further,a base may be added to the reaction, and examples of such a base includeorganic bases, inorganic bases and the like.

When boration reaction is carried out in each step, examples of themetal catalyst to be used include palladium compounds such astetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0) and1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride. Further, abase may be added to the reaction, and examples of such a base includeorganic bases, inorganic bases and the like. In addition, examples ofthe boron source include pinacol diborane. Moreover, a borate estergroup can be transformed into a boric acid group using ammonium acetateand sodium periodate as reagents.

When cyanation reaction is carried out in each step, examples of themetal catalyst to be used include palladium compounds such as palladiumacetate, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0) and1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride; andcyanides such as sodium cyanide, zinc cyanide and copper cyanide. Inaddition, a phosphine ligand such as1,1′-bis(diphenylphosphino)ferrocene or zinc powder may be added to thereaction.

Compound (I) can be produced by, for example, the following method.

Production Method 1

Compound (Ia), compound (Ib) and compound (Ic), in which R¹ of compound(I) is a hydroxy group, ORy and NHRy, respectively, can be produced bythe following method.

wherein Re represents an optionally substituted C₁₋₆ alkyl group (forexample, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), allylgroup or benzyl group, and the other symbols are as defined above.

Production Method 2

Compound (Ie), in which X of compound (Id) is C(═O), can be produced bythe following method.

wherein Rd represents an optionally substituted C₁₋₆ alkyl group (forexample, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), allylgroup or benzyl group; Rf represents a tert-butoxy group or benzyloxygroup; and the other symbols are as defined above.

Production Method 3

Compound (Ii), in which R² and R³ of compound (If) are hydrogen, can beproduced by the following method.

wherein X1 represents a chlorine atom, a bromine atom, a iodine atom, anoptionally substituted sulfonyloxy group (for example,methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy,benzenesulfonyloxy, p-toluenesulfonyloxy and the like); B1 represents aboron group (for example, potassium trifluoroborate (—BF₃K), boronicacid group (—B(OH)₂), borate ester group (—B(OR′)₂, wherein R′represents a C₁₋₆ alkyl group) or cyclic group thereof (for example,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and the like); and the othersymbols are as defined above.

Production Method 4

Compound (Il) can be produced by the following method.

wherein the symbols in the formula are as defined above.

Production Method 5

-   Compound (Ij) can be produced by the following method.

wherein the symbols in the formula are as defined above.

Production Method 6

-   Compound (Iq), in L of compound (Ij) is    —CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—*, can be produced by the following    method.

wherein the symbols in the formula are as defined above.

Production Method 7

Compound (If) can be produced by the following method.

wherein the symbols in the formula are as defined above.

In addition, in a step of producing compound (I) from ingredientcompounds and/or production intermediates of compound (I), compound (I)can be synthesized, if desired, by singly carrying out reductionreaction, oxidation reaction, Wittig reaction, Horner-Emmons reaction,protection reaction, nucleophilic aromatic substitution reaction,nucleophilic addition reaction with carbanion, Grignard reaction,azidation reaction, reductive amination reaction, Claisen rearrangementreaction, Mitsunobu reaction, Wohl-Ziegler reaction, sulfonateesterification reaction, Staudinger reaction, halogenation reaction ofhydroxy group, dehydration reaction, cyclization reaction orring-closing metathesis reaction, or by carrying out two or more of themin combination, depending on various substituents that compound (I) mayhave.

When reduction reaction is carried out in each step, examples of thereducing agent to be used include iron; metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminium hydride (DIBAL-H), sodium borohydride andtetramethylammonium triacetoxyborohydride; boranes such as boranetetrahydrofuran complex; Raney nickel; Raney cobalt; Pd/C; PtO₂; zinc;hydrogen; formic acid; and triethylsilane. When a carbon-carbon doublebond or triple bond is reduced, the reduction reaction may be carriedout by a method using a catalyst such as palladium-carbon, Lindlarcatalyst and the like. When a nitro group is reduced, the reductionreaction may also be carried out by using iron and ammonium chloride.When a cyano group is reduced, the reduction reaction may also becarried out by using the reducing agents described above and sodiumphosphinate. When a carboxylic acid is reduced, the reduction reactionmay also be carried out by, after making a mixed acid anhydride withisobutyl chloroformate or the like, using sodium borohydride. This stepcan be carried out by using only one of the reagents, or by using two ormore of them in combination.

When oxidation reaction is carried out in each step, examples of theoxidizing agent to be used include peracids such as m-chloroperbenzoicacid (mCPBA), hydrogen peroxide and tert-butyl hydroperoxide;perchlorates such as tetrabutylammonium perchlorate; chlorates such assodium chlorate; chlorites such as sodium chlorite; periodates such assodium periodate; high valent iodine reagents such as iodosylbenzene;reagents having manganese such as manganese dioxide and potassiumpermanganate; leads such as lead tetraacetate; reagents having chromiumsuch as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC) andJones reagent; halogen compounds such as N-bromosuccinimide (NBS);oxygen; ozone; sulfur trioxide-pyridine complex; oxalylchloride-dimethylsulfoxide; osmium tetroxide; selenium dioxide; and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

When Wittig reaction is carried out in each step, examples of the Wittigreagent to be used include alkylidene phosphoranes. Alkylidenephosphoranes can be prepared by a method known per se, for example, byallowing a phosphonium salt to react with a strong base.

When Horner-Emmons reaction is carried out in each step, examples of thereagent to be used include phosphonoacetate esters such as methyldimethylphosphonoacetate and ethyl diethylphosphonoacetate; and basessuch as alkali metal hydrides and organic lithiums.

When nucleophilic aromatic substitution reaction is carried out in eachstep, for the reagent, a nucleophile (for example, an amine) and a base(for example, an inorganic base, an organic base and the like) are used.

When nucleophilic addition reaction with carbanion, nucleophilic1,4-addition reaction with carbanion (Michael addition reaction) ornucleophilic substitution reaction with carbanion is carried out in eachstep, examples of the base to be used for generating carbanion includeorganic lithiums, metal alkoxides, inorganic bases, and organic bases.

When Grignard reaction is carried out in each step, examples of theGrignard reagent include aryl magnesium halides such as phenyl magnesiumbromide; and alkyl magnesium halides such as methyl magnesium bromide.The Grignard reagent can be prepared by a method known per se, forexample, by allowing an alkyl halide or an aryl halide to react with ametal magnesium in ether or tetrahydrofuran as a solvent.

When azidation reaction of an alcohol, an alkyl halide or a sulfonateester is carried out in each step, examples of the azidation agent to beused include diphenylphosphoryl azide (DPPA), trimethylsilyl azide andsodium azide. For example, when an alcohol is azidated, the azidationreaction may be carried out by a method using diphenylphosphoryl azideand 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), a method usingtrimethylsilyl azide and a Lewis acid, or the like.

When reductive amination reaction is carried out in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen and formic acid. When the substrate isan amine compound, examples of the carbonyl compound to be used include,in addition to paraformaldehyde, aldehydes such as acetaldehyde andketones such as cyclohexanone. When the substrate is a carbonylcompound, examples of the amine to be used include ammonia; primaryamines such as methylamine; and secondary amines such as dimethylamine.

When Mitsunobu reaction is carried out in each step, azodicarboxylateesters (for example, diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) and the like) and triphenylphosphine are used asreagents.

When Wohl-Ziegler reaction is carried out in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine andsulfuryl chloride. Further, the reaction can be accelerated by addingheat, light, radical initiators such as benzoyl peroxide andazobisisobutyronitrile to the reaction.

When halogenation reaction of hydroxy group is carried out in each step,examples of the halogenating agent to be used include a hydrohalic acidand an acid halide of an inorganic acid; specifically, hydrochloricacid, thionyl chloride and phosphorus oxychloride for chlorination, and48% hydrobromic acid for bromination. In addition, a method of obtainingan alkyl halide form from an alcohol through the action betweentriphenylphosphine and carbon tetrachloride, carbon tetrabromide or thelike may be used. Alternatively, a method of synthesizing an alkylhalide form over the course of two-step reaction including converting analcohol into a sulfonate ester, and allowing it to react with lithiumbromide, lithium chloride or sodium iodide may also be used.

When sulfonate esterification reaction is carried out in each step,examples of the sulfonylating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride andp-toluenesulfonic anhydride.

When dehydration reaction is carried out in each step, examples of thedehydrating agent to be used include sulfuric acid, phosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina and polyphosphoric acid.

When cyclization reaction is carried out in each step, sodium nitrite isused as a reagent, and an acidic solvent such as acetic acid andhydrochloric acid is used as a solvent.

When Staudinger reaction is carried out in each step, examples of thereagent include phosphines such as triphenylphosphine and water.

When ring-closing metathesis reaction is carried out in each step, forthe metal catalyst to be used, a ruthenium compound such as Grubbs1st-generation catalyst, Grubbs 2nd-generation catalyst andGrubbs-Hoveyda 2nd-generation catalyst is used.

When Claisen rearrangement reaction is carried out in each step, thereaction can be carried out by heating a reaction solution formed of theingredients and solvent.

When nucleophilic addition reaction with carbanion, nucleophilic1,4-addition reaction with carbanion (Michael addition reaction) ornucleophilic substitution reaction with carbanion is carried out in eachstep, examples of the base to be used for generating carbanion includeorganic lithiums, metal alkoxides, inorganic bases, and organic bases.

Ingredient compounds and/or production intermediates of compound (I) maybe in the salt forms, and although they are not particularly limited aslong as the reaction is achieved, for example, salts and the like areused that are the same as salts that compound (I) and the like may form.

In the ingredient compounds and/or production intermediates of compound(I), configurational isomers (E, Z forms) may be generated, and at thetime point where configurational isomers (E, Z forms) are generated,they can be isolated and purified by normal separating means such asextraction, recrystallization, distillation and chromatography toproduce a pure compound. In addition, isomerization of the double bondcan be advanced through heating, an acid catalyst, a transition metalcomplex, a metal catalyst, a radical species catalyst, photoirradiation,a strong base catalyst or the like to obtain a corresponding pure isomerin accordance with the methods described in The New ExperimentalChemistry, vol. 14 (edited by The Chemical Society of Japan), pp.251 to253; The Fourth Series of Experimental Chemistry, vol. 19 (edited by TheChemical Society of Japan), pp.273 to 274, and methods equivalentthereto.

When a target compound is obtained in the free form through thereactions described above, it may be transformed into a salt inaccordance with a normal method, and when a target compound is obtainedin the form of salt, it can be transformed into a free form or anothersalt in accordance with a normal method. Compound (I) obtained as suchcan be isolated or purified from the reaction solution by any knownmeans, for example, solvent transition, concentration, solventextraction, fractional distillation, crystallization, recrystallization,chromatography or the like.

Compound (I) obtained as such, other reaction intermediates andingredient compounds thereof can be isolated or purified from thereaction mixture in accordance with a method known per se, for example,by using a means such as extraction, concentration, neutralization,filtration, distillation, recrystallization, column chromatography, thinlayer chromatography, preparative high performance liquid chromatography(preparative HPLC) and moderate pressure preparative liquidchromatography (moderate pressure preparative LC).

Compound (I) may be in the form of salt, and a salt of compound (I) canbe produced according to a method known per se. For example, whencompound (I) is a basic compound, it can be produced by adding aninorganic acid or organic acid, or when compound (I) is an acidiccompound, it can be produced by adding an organic base or inorganicbase.

When compound (I) is a solvate (for example, hydrate), a solvate of thetarget compound can be isolated from the reaction mixture by variousmethods such as distillation and crystallization after allowing theingredient compounds to react in an appropriate solvent. A non-solvatecan be produced by desolvation transition of a solvate throughtemperature rising, drying or the like.

When compound (I) may have enantiomers, individual enantiomers and amixture thereof are of course all encompassed in the scope of thepresent invention, and these isomers may be subjected to opticalresolution or may be produced individually, in accordance with a methodknown per se, if desired.

When compound (I) is present as configurational isomers, diastereomers,conformers or the like, they can be isolated in accordance with theseparation or purification means described above, if desired. Inaddition, when compound (I) is a racemate, it can be isolated intoS-form and R-form in accordance with a normal optical resolution means.

When compound (I) has stereoisomers, the present invention encompasses asingle stereoisomer and a mixture thereof.

Compound (I) may be a prodrug. The prodrug refers to a compound that isconverted into compound (I) as a result of reaction with an enzyme,gastric acid or the like under physiological conditions in vivo, thatis, a compound that undergoes enzymatic oxidation, reduction, hydrolysisor the like to be converted into compound (I) and a compound thatundergoes hydrolysis or the like by gastric acid or the like to beconverted into compound (I).

Examples of the prodrug for compound (I) include compounds with an aminogroup in compound (I) acylated, alkylated and phosphorylated (forexample, compounds with an amino group in compound (I) eicosanoylated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,tert-butylated and the like); compounds with a hydroxyl group incompound (I) acylated, alkylated, phosphorylated and borated (forexample, compounds with a hydroxy group in compound (I) acetylated,palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,alanylated, dimethylaminomethylcarbonylated and the like); and compoundswith a carboxyl group in compound (I) esterified and amidated (forexample, compounds with a carboxyl group in compound (I) ethylesterified, phenyl esterified, carboxymethyl esterified,dimethylaminomethyl esterified, pivaloyloxymethyl esterified,ethoxycarbonyloxyethyl esterified, phthalidyl esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified,cyclohexyloxycarbonylethyl esterified, methylamidated and the like).These compounds can be produced from compound (I) according to a knownmethod. In addition, a prodrug of compound (I) may also be one that isconverted into compound (I) under physiological conditions as describedin “Pharmaceutical Research and Development”, vol. 7, Design ofMolecules, pp.163-198, issued in 1990 by HIROKAWA SHOTEN.

Compound (I) or a prodrug thereof (hereinafter, may be simplyabbreviated as the inventive compound) can have an excellent NRF2activating activity in vivo, and can be useful as a preventive ortherapeutic agent for diseases associated with oxidative stress.

The inventive compound is expected to be excellent in pharmacokinetics(for example, oral absorbability, drug half-life in blood, intracerebraltransferability, metabolic stability) and have low toxicity (forexample, acute toxicity, chronic toxicity, genetic toxicity,reproductive toxicity, cardiotoxicity, drug interaction,carcinogenicity), and can be safely administered orally or parenterallyto a mammal (for example, human, monkey, cattle, horse, pig, mouse, rat,hamster, rabbit, cat, dog, sheep, goat) as a medicament with no changeor as a pharmaceutical composition formed by mixing the inventivecompound with a pharmaceutically acceptable carrier or the like.Examples of the “parenteral” administration include sublingual,intravenous, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, intrarectal, intravaginal,intraperitoneal and intratumor administrations, administration to thevicinity of tumor and the like, and direct administration to the lesion.

It is believed that the inventive compound has a fixed conformationbecause it has a macrocyclic structure, and has an excellent NRF2activating activity, and therefore, it can exhibit effectiveness inprevention or treatment for diseases associated with oxidative stressand caused by oxidative stress, such as hepatic disease (for example,hepatitis (for example, non-alcoholic steatohepatitis, fatty liver,alcoholic hepatitis, hepatitis B, hepatitis C, hepatic veno-occlusivedisease), hepatic cirrhosis, bile duct disease (for example, primarysclerosing cholangitis (PSC)), cardiovascular disease (for example,heart failure, pulmonary arterial hypertension, myocardial infarction,arteriosclerosis, angina pectoris, brain infarction, cerebralhemorrhage, aortic aneurysm, aortic dissection, nephrosclerosis (forexample, hypertensive nephrosclerosis), peripheral arterial disease(PAD), arteriosclerosis obliterans, dysrhythmia), lung disease (forexample, chronic obstructive pulmonary disease (COPD), idiopathicpulmonary fibrosis (IPF), cystic fibrosis, asthma, pneumonia, aspirationpneumonia, interstitial pneumonia, respiratory infection, acute lunginjury, acute respiratory distress syndrome (ARDS), α1-antitrypsindeficiency), kidney disease (for example, chronic kidney disease (CKD),diabetic kidney disease (DKD), acute kidney injury (AKI), glomerularnephritis, pyelonephritis, interstitial nephritis, glomerulosclerosis,nephrotic syndrome, lupus nephritis, Alport syndrome, IgA nephropathy,polycystic kidney), central nervous system disease (for example,Parkinson's disease, Alzheimer's disease, dementia, cerebral stroke,amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD),polyglutamine disease, prion disease, Huntington's disease, traumaticbrain injury, epilepsy, autism, depression, adrenoleukodystrophy),mitochondrial disease (for example, Friedreich motor ataxia,mitochondrial myopathy), inflammatory disease (for example, multiplesclerosis, chronic rheumatism, systemic lupus erythematosus, Sjoegrensyndrome, scleroderma, autoimmune hepatitis, type 1 diabetes mellitus,ulcerous colitis, Crohn disease, inflammatory bowel disease (IBD),spondylarthritis, pollinosis, collagen disease), life style relateddisease (for example, diabetes mellitus, hyperlipidemia, obesity, highblood pressure, hypercholesterolemia) and complication thereof (forexample, diabetic retinopathy, DKD, diabetic neuropathy), sickle celldisease, thalassemia, anemia (for example, aplastic anemia, hemolyticanemia), cancer (for example, liver cancer, lung cancer, renal cancer,colon cancer, melanoma, medulloblastoma, neuroblastoma, leukemia),cachexia, gastrointestinal disease (for example, functionalgastrointestinal disorder, gastric ulcer, reflux esophagitis,pancreatitis), endocrine disease (for example, Cushing syndrome,Hashimoto disease), eye disease (for example, age-related maculardegeneration, corneal endothelial disorder, Fuchs endothelial cornealdystrophy (FECD), eye inflammation, ophthalmalgia, retinopathy ofprematurity, cataract, dry eye), skin disease (for example, psoriasis,dermatitis, radiation dermatitis, epidermolysis bullosa, atopicdermatitis, stomatitis), wound healing failure, bone disease (forexample, osteoporosis, systemic bone disease, bone fracture), viralinfection (for example, HIV virus, cytomegalovirus, respiratorysyncytial virus, influenza virus), heavy metal poisoning (for example,lead poisoning, mercury poisoning), pesticide poisoning (for example,paraquat poisoning, organophosphorus poisoning), drug-induced disorder(for example, drug-induced renal disorder, drug-induced hepatic disorder(for example, hepatic disorder due to acetaminophen), drug-induced lungdisorder, orthopedic disease (for example, low back pain, sciaticneuralgia, intervertebral disk displacement, neck ache, stiff shoulder),pain (for example, fibromyalgia, neuropathic pain), ischemia-reperfusioninjury and shock upon organ transplantation and surgery, aging,progeria, hyperanakinesia (for example, sarcopenia), urologic disease(for example, urination disorder), dental disease (for example,periodontal disease), otolaryngologic disease (for example, hearingdifficulty), altitude sickness, chronic fatigue syndrome, and thinninghair. In addition, the inventive compound can exhibit enhancement of theeffect of cancer treatment and the effect of improving survival rate bya combined use with an immunity anticancer agent (for example, immunecheckpoint inhibiting antibody). Further, it can exhibit a regenerationpromoting activity (for example, hepatic regeneration promoting agentafter hepatectomy).

In particular, the inventive compound can be, based on its NRF2activating activity, useful as a preventive or therapeutic agent forhepatic disease (for example, non-alcoholic steatohepatitis (NASH),alcoholic hepatitis, drug-induced hepatic disorder), bile duct disease(for example, primary sclerosing cholangitis (PSC)), cardiovasculardisease (for example, heart failure or pulmonary arterial hypertension),lung disease (for example, chronic obstructive pulmonary disease(COPD)), kidney disease (for example, chronic kidney disease (CKD) oracute kidney injury (AKI)), acetaminophen poisoning, central nervoussystem disease (for example, Parkinson's disease, Alzheimer's disease,cerebral stroke), mitochondrial disease (for example, Friedreich motorataxia, mitochondrial myopathy), inflammatory disease (for example,multiple sclerosis, inflammatory bowel disease (IBD)), sickle celldisease, or the like.

The dosage of the inventive compound varies depending on anadministration route, symptom and the like. For example, for oraladministration to a patient with hepatitis (adult, body weight 40 to 80kg, for example, 60 kg), the dosage is, for example, 0.001 to 1000 mg/kgbody weight/day, preferably 0.01 to 100 mg/kg body weight/day, andfurther preferably 0.1 to 10 mg/kg body weight/day. This amount can beadministered in one to three portions per day.

A medicament containing the inventive compound may be used as theinventive compound solely or as a pharmaceutical composition formed bymixing the inventive compound with a pharmaceutically acceptable carrierin accordance with a method (for example, the methods described in ThePharmacopoeia of Japan) that is known per se as a method of producing apharmaceutical formulation. The medicament containing the inventivecompound can be safely administered orally or parenterally (for example,intravenous, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, intrarectal, intravaginal andintraperitoneal administrations, and administration to the lesion) inthe form of, for example, tablet (including sugar-coated tablet,film-coated tablet, sublingual tablet, orally disintegrating tablet,buccal or the like), pill, powder, granule, capsule (including softcapsule, microcapsule), troche, syrup, liquid, emulsion, suspension,release control formulation (for example, immediate-release formulation,sustained-release formulation, sustained-release microcapsule), aerosol,film (for example, orally disintegrating film, oral mucosa-adhesivefilm), injection (for example, subcutaneous injection, intravenousinjection, intramuscular injection, intraperitoneal injection), dripinfusion, transdermal absorption type formulation, ointment, lotion,patch, suppository (for example, rectal suppository, vaginalsuppository), pellet, nasal formulation, pulmonary formulation(inhalant), eye drop or the like.

For the “pharmaceutically acceptable carrier” described above, a varietyof organic or inorganic carriers that have been conventionally used asformulation materials (starting materials) are used. For example, anexcipient, a lubricant, a binder, a disintegrant and the like are usedfor a solid formulation, and a solvent, a dissolving aid, a suspendingagent, an isotonizing agent, a buffering agent, a soothing agent and thelike are used for a liquid formulation. In addition, as necessary,formulation additives such as a preservative, an antioxidant, a colorantand a sweetening agent can also be used.

Examples of the excipient include lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose and light anhydrous silicicacid.

Examples of the lubricant include magnesium stearate, calcium stearate,talc and colloidal silica.

Examples of the binder include crystalline cellulose, white sugar,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose and sodium carboxymethyl cellulose.

Examples of the disintegrant include starch, carboxymethyl cellulose,calcium carboxymethyl cellulose, sodium carboxymethyl starch andL-hydroxypropyl cellulose.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil and olive oil.

Examples of the dissolving aid include polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane,cholesterol, triethanolamine, sodium carbonate and sodium citrate.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride and glycerinmonostearate; and hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylcellulose.

Examples of the isotonizing agent include glucose, D-sorbitol, sodiumchloride, glycerin and D-mannitol.

Examples of the buffering agent include buffering solutions of phosphatesalt, acetate salt, carbonate salt and citrate salt.

Examples of the soothing agent include benzyl alcohol.

Examples of the preservative include para-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acidand sorbic acid.

Examples of the antioxidant include sulfite salt, ascorbic acid,a-tocopherol.

The pharmaceutical composition can be produced in accordance with anormal method by adding the inventive compound in a proportion ofnormally 0.01 to 100% (w/w) and preferably 0.1 to 95% (w/w) relative tothe whole amount of the formulation although the proportion variesdepending on the dosage from, administration method, carrier and thelike.

The inventive compound may be used in combination with another activeingredient (hereinafter, abbreviated as a concomitant drug).

As the concomitant drug, a compound that may have a preventive and/ortherapeutic effect against oxidative stress diseases or a salt thereofcan be appropriately compounded depending on the disease to be atreatment target. Examples of the compound that may have a preventiveand/or therapeutic effect against oxidative stress diseases or a saltthereof include cardiotonic agents such as digoxin, β agonists such asdobutamine, β inhibitors such as carvedilol, vasodilator drugs such asnitroglycerin, prostacyclin and riociguat, angiotensin converting enzymeinhibitors such as ramipril, angiotensin II receptor antagonists such ascandesartan, diuretic drugs such as hydrochlorothiazide and furosemide,calcium receptor antagonists such as amlodipine, mineralocorticoidreceptor antagonists such as eplerenone, endothelin receptor antagonistssuch as bosentan, anticoagulant drugs such as rivaroxaban, antiplateletdrugs such as clopidogrel, antidiabetic drugs such as metformin,alogliptin, pioglitazone and ipragliflozin, dyslipidemia improving drugssuch as atorvastatin, fenofibrate, ezetimibe and niacin,anti-inflammatory drugs such as roflumilast, adrenergic β-2 receptoragonists such as salbutamol, steroidal formulations, Dopamine precursorssuch as levodopa, monoamine oxidase B inhibitors such as selegiline, andanticholinergic drugs such as biperiden. Other examples of theconcomitant drug include immune checkpoint inhibitors such as anti-PD-1antibodies, anti-PD-L1 antibodies and anti-CTLA-4 antibodies.

By combining the inventive compound with a concomitant drug, excellenteffects can be achieved, such as:

-   (1) the dosage can be reduced as compared to single administration    of the inventive compound or a concomitant drug;-   (2) the drug to be combined with the inventive compound can be    selected depending on symptoms of the patient (mild symptom, severe    symptom and the like);-   (3) the treatment duration can be set long by selecting a    concomitant drug having an action mechanism different from that of    the inventive compound;-   (4) a sustained treatment effect can be designed by selecting a    concomitant drug having an action mechanism different from the    inventive compound; and-   (5) a synergistic effect can be afforded by a combined use of the    inventive compound and a concomitant drug.

Hereinafter, using the inventive compound with a concomitant drug incombination is referred to as a “combination agent according to thepresent invention”.

Upon using the combination agent according to the present invention,administration time of the inventive compound and the concomitant drugis not limited, and the inventive compound or a pharmaceuticalcomposition thereof and the concomitant drug or a pharmaceuticalcomposition thereof may be administered to an administration subjectsimultaneously, or may be administered with time difference. The dosageof the concomitant drug may be determined in accordance with a dosagethat is clinically used, and can be appropriately selected depending onan administration subject, administration route, disease, combinationand the like.

The administration mode of the combination agent according to thepresent invention is not particularly limited, and it is sufficient thatthe inventive compound and the concomitant drug are combined uponadministration. Examples of such an administration mode include (1)administration of a single formulation obtained by simultaneouslyformulating the inventive compound and the concomitant drug, (2)simultaneous administration of two kinds of formulations obtained byseparately formulating the inventive compound and the concomitant drugthrough the same administration route, (3) administration of two kindsof formulations obtained by separately formulating the inventivecompound and the concomitant drug through the same administration routebut with time difference, (4) simultaneous administration of two kindsof formulations obtained by separately formulating the inventivecompound and the concomitant drug through different administrationroutes, (5) administration of two kinds of formulations obtained byseparately formulating the inventive compound and the concomitant drugthrough different administration routes with time difference (forexample, administration of the inventive compound and the concomitantdrug in the order described, or in the reverse order) and the like.

The combination agent according to the present invention has lowtoxicity. For example, the inventive compound or(and) the concomitantdrug described above can be combined with a pharmacologically acceptablecarrier according to a known method to prepare a pharmaceuticalcomposition such as a tablet (including sugar-coated tablet andfilm-coated tablet), powder, granule, capsule (including soft capsule),liquid, injection, suppository, sustained-release agent and the like.These compositions can be safely administered orally or parenterally(for example, topical, rectal, intravenous administration). Theinjection can be administered intravenously, intramuscularly,subcutaneously, or by intraorgan administration or direct administrationto the lesion.

Examples of the pharmacologically acceptable carrier that may be usedfor production of the combination agent according to the presentinvention include a variety of organic or inorganic carrier substancesthat are conventionally used as formulation materials. For example, anexcipient, a lubricant, a binder and a disintegrant can be used for asolid formulation. For a liquid formulation, a solvent, a dissolvingaid, a suspending agent, an isotonizing agent, a buffering agent, asoothing agent and the like can be used. Further, as necessary, normaladditives such as a preservative, an antioxidant, a colorant, asweetening agent, an adsorbent, and a wetting agent can be appropriatelyused in an appropriate amount.

Examples of the excipient include lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose and light anhydrous silicicacid.

Examples of the lubricant include magnesium stearate, calcium stearate,talc and colloidal silica.

Examples of the binder include crystalline cellulose, white sugar,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose and sodium carboxymethyl cellulose.

Examples of the disintegrant include starch, carboxymethyl cellulose,calcium carboxymethyl cellulose, sodium carboxymethyl starch andL-hydroxypropyl cellulose.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil and olive oil.

Examples of the dissolving aid include polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane,cholesterol, triethanolamine, sodium carbonate and sodium citrate.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride and glycerinmonostearate; and hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylcellulose.

Examples of the isotonizing agent include glucose, D-sorbitol, sodiumchloride, glycerin and D-mannitol.

Examples of the buffering agent include buffering solutions of phosphatesalt, acetate salt, carbonate salt and citrate salt.

Examples of the soothing agent include benzyl alcohol.

Examples of the preservative include para-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acidand sorbic acid.

Examples of the antioxidant include sulfite salt, ascorbic acid,α-tocopherol.

The mixing ratio of the inventive compound and the concomitant drug inthe combination agent according to the present invention can beappropriately selected depending on an administration subject,administration route, disease and the like.

For example, the content of the inventive compound in the combinationagent according to the present invention varies depending on the form ofthe formulation, but is normally from about 0.01 to 100% by weight,preferably from about 0.1 to 50% by weight, and further preferablyapproximately from about 0.5 to 20% by weight relative to the entireformulation.

The content of the concomitant drug in the combination agent accordingto the present invention varies depending on the form of theformulation, but is normally from about 0.01 to 100% by weight,preferably from about 0.1 to 50% by weight, and further preferablyapproximately from about 0.5 to 20% by weight relative to the entireformulation.

The content of additives such as a carrier in the combination agentaccording to the present invention varies depending on the form of theformulation, but is normally from about 1 to 99.99% by weight, andpreferably approximately from about 10 to 90% by weight relative to theentire formulation.

In addition, when the inventive compound and the concomitant drug areseparately formulated, the contents thereof may be the same as above.

EXAMPLES

The present invention will be further described in detail with referenceto the following Examples, Test Examples, and Formulation Examples.However, they do not limit the present invention, and may be varied inthe range without departing the scope of the present invention.

In the following Examples, “room temperature” normally indicates about10° C. to about 35° C. Ratios shown in mixed solvents indicate volumeratios unless otherwise noted. % indicates % by weight unless otherwisenoted.

Elution in column chromatography in Examples were carried out underobservation by TLC (Thin Layer Chromatography) unless otherwisementioned. In the TLC observation, 60 F254 manufactured by Merck KGaAwas used as a TLD plate, and a solvent that was used as an elutingsolvent in column chromatography was used as a developing solvent. Inaddition, an UV detector was employed for detection. In silica gelcolumn chromatography, when NH is described, aminopropylsilane-bindingsilica gel was used, and when Diol is described,3-(2,3-dihydroxypropoxy)propylsilane-binding silica gel was used. InHPLC (High Performance Liquid Chromatography), when C18 is described,octadecyl-binding silica gel was used. Ratios of eluting solventsindicate volume ratios unless otherwise noted.

In the following Examples, abbreviations described below will be used.

-   mp: melting point-   MS: mass spectrum-   M: molar concentration-   N: normality-   CDCl₃: deuterated chloroform-   DMSO-d₆: deuterated dimethylsulfoxide-   ¹H NMR: proton nuclear magnetic resonance-   LC/MS: liquid chromatograph mass spectrometer-   ESI: electrospray ionization-   EtOAc: ethyl acetate-   APCI: atmospheric pressure chemical ionization-   DMF: N,N-dimethylformamide-   DMSO: dimethylsulfoxide-   DMAP: N,N-dimethylamino-4-aminopyridine-   Et: ethyl-   EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HOBt: 1-hydroxybenzotriazole-   PPh₃: triphenylphosphine-   THF: tetrahydrofuran-   CPME: cyclopentyl methyl ether-   AcOH: acetic acid-   HPLC: high performance liquid chromatogram-   Boc: tert-butoxycarbonyl-   Ts: p-toluenesulfonyl-   TBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide    tetrafluoroborate-   KHMDS: potassium hexamethyl disilazide-   BuLi: butyllithium-   COD: 1,5-cyclooctadiene-   DCM: dichloromethane-   DEAD: diethyl azodicarboxylate-   DIPEA: diisopropylethylamine-   DMA: N,N-dimethylacetamide-   dba: dibenzylideneacetone-   dppf: 1,1′-bis(diphenylphosphino)ferrocene-   iPr: isopropyl-   NBS: N-bromosuccinimide-   NMM: N-methylmorpholine-   TFA: Trifluoroacetic acid-   TLC: thin-layer chromatography-   TMS: Trimethylsilyl-   Reverse phase preparative HPLC: Method A-   Preparative HPLC was done on Waters auto purification instrument.    Column name: YMC Triart C18 (100×30 mm, 5 μm) operating at ambient    temperature and flow rate of 30 mL/min. Mobile phase: A=20 mM    Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile:    Mobile phase initial composition of 80% A and 20% B, then 60% A and    40% B in 2 min, then to 20% A and 80% B in 12 min., then to 5% A and    95% B in 13 min., held this composition up to 15 min. for column    washing, then returned to initial composition in 16 min. and held    till 18 min.

Reverse Phase Chiral Preparative HPLC: Method B

-   Preparative HPLC was done on Waters auto purification instrument.    Column name: REFLECT I CELLULOSE C (250×21.2 mm, 5 μm) operating at    ambient temperature and flow rate of 16 mL/min. Mobile phase: A=0.1%    TFA in water, B=Acetonitrile; Gradient Profile: Mobile phase initial    composition of 80% A and 20% B, then 70% A and 30% B in 2.5 min,    then to 55% A and 45% B in 6 min., then to 15% A and 85% B in 25    min., then to 5% A and 95% B in 26 min., held this composition up to    30 min. for column washing, then returned to initial composition in    30.5 min. and held till 36 min.

Normal Phase Chiral Preparative HPLC: Method C

-   Preparative HPLC was done on Agilent Prep-HPLC. Column name:    Chiralpak IA (21.0×250 mm, 5 μm) operating at ambient temperature    and flow rate of 21 mL/min. Mobile phase: Hexane/DCM/EtOH/TFA :    70/15/15/0.1; Gradient Profile: Mobile phase initial composition of    80% A and 20% B, then 70% A and 30% B in 2.5 min, then to 55% A and    45% B in 6 min., then to 15% A and 85% B in 25 min., then to 5% A    and 95% B in 26 min., held this composition up to 30 min. for column    washing, then returned to initial composition in 30.5 min. and held    till 36 min.

Normal Phase Chiral Preparative HPLC: Method D

Chiral HPLC was carried out on Waters Manual purification system with2545 Quaternary Gradient Pump and 2489 UV Detector. Column name:Chiralpak IA (250×21.2 mm, 5 μm) operating at ambient temperature andflow rate of 26 mL/min. Mobile phase: A=Ethanol, B=0.1% TEA in n-Hexane;Isocratic Profile: A : B=30%: 70%, same composition was held up for thetotal runtime of 35 min. Detector was programmed at compound'swavelength i.e. 293 nm and sample preparation was done by using Methanoland DCM.

For ¹H NMR, Fourier transform NMR was used for measurement. Foranalysis, ACD/SpecManager (product name) or the like was used. Verygentle peaks of protons such as those for hydroxy groups or amino groupsare not described.

MS was measured by LC/MS. For ionization method, ESI method or APCImethod was used. For data, measured values (found) are described.Normally, molecular ion peaks (such as [M+H]⁺ and [M−H]⁻) are observed,but for example, in the case of a compound having a tert-butoxycarbonylgroup, a peak for which a tert-butoxycarbonyl group or tert-butyl groupis desorbed may be observed as a fragment ion, and in the case of acompound having a hydroxy group, a peak for which H₂O is desorbed may beobserved as a fragment ion. In the case of a salt, the molecular ionpeak of the free form or a fragment ion peak is normally observed.

The unit of sample concentration (c) in optical rotation ([α]_(D)) isg/100 mL.

For the elementary analysis value (Anal.), calculated values (Calcd) andmeasured values (Found) are described.

The powder X-ray diffraction pattern was measured by using Cu-Kαcharacteristic X-ray of Rigaku Ultima IV, and characteristic peaks aredescribed.

Example 1[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

A) tert-Butyl 4-(5-hydroxypent-1-yn-1-yl)benzoate

A mixture of tert-butyl 4-iodobenzoate (3.68 g), 4-pentyn-1-ol (1.32 g),PdCl₂(PPh₃)₂ (425 mg), copper iodide (46.1 mg), and triethylamine (20ml) was stirred at room temperature overnight. To the mixture was addedethyl acetate at room temperature, and the reaction mixture was washedwith saturated aqueous ammonium chloride solution and saturated brine,followed by drying over anhydrous magnesium sulfate and concentrationunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (3.15g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.54 (9H, s), 1.64-1.76 (2H, m), 2.45-2.49(2H, m), 3.47-3.56 (2H, m), 4.56 (1H, t, J=5.2 Hz), 7.49 (2H, d, J=8.1Hz), 7.85 (2H, d, J=8.1 Hz).

B) tert-Butyl 4-(5-hydroxypentyl)benzoate

tert-Butyl 4-(5-hydroxypent-1-yn-1-yl)benzoate (3.15 g) and a suspensionof palladium/carbon (500 mg) in ethanol (50 ml) were stirred underhydrogen atmosphere overnight. Palladium/carbon was removed and thereaction mixture was concentrated under reduced pressure to give thetitle compound (3.05 g).

¹ H NMR (300 MHz, DMSO-d₆) δ 1.23-1.34 (2H, m), 1.37-1.49 (2H, m),1.51-1.65 (11H, m), 2.63 (2H, t, J=7.3 Hz), 3.34-3.41 (2H, m), 4.34 (1H,t, J=4.9 Hz), 7.31 (2H, d, J=7.9 Hz), 7.81 (2H, d, J=8.0 Hz).

C) tert-Butyl 4-{5-[(4-methylbenzene-1-sulfonyl)oxy]pentyl}benzoate

To a solution of tert-butyl 4-(5-hydroxypentyl)benzoate (22.4 g) intetrahydrofuran (200 ml), triethylamine (17.2 g), p-toluenesulfonylchloride (19.4 g) and 4-dimethylaminopyridine (1.04 g) were added atroom temperature, and the reaction mixture was stirred at roomtemperature for 2 hours. Then, p-toluenesulfonyl chloride (19.4 g) andtriethylamine (8.6 g) were added thereto, and the reaction mixture wasfurther stirred at 60° C. for 3 hours. To the reaction solution,triethylamine (8.6 g) and p-toluenesulfonyl chloride (19.4 g) werefurther added, and the reaction solution was stirred at 50° C. for 5hours. To the mixture was added ethyl acetate at room temperature, andthe reaction mixture was washed with water and saturated brine, followedby drying over anhydrous magnesium sulfate and concentration underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (30.2g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.19-1.32 (2H, m), 1.39-1.67 (13H, m), 2.41(3H, s), 2.56 (2H, br t, J=7.5 Hz), 4.00 (2H, t, J=6.2 Hz), 7.26 (2H, d,J=7.8 Hz), 7.47 (2H, br d, J=7.9 Hz), 7.79 (4H, br t, J=9.0 Hz).

D) tert-Butyl 4-(5-azidopentyl)benzoate

To a solution of tert-butyl4-{5-[(4-methylbenzene-1-sulfonyl)oxy]pentyl}benzoate (30.2 g) inN,N-dimethylformamide (150 ml), sodium iodide (10.8 g) and sodium azide(9.39 g) were added, and the reaction mixture was stirred at 90° C. for3 hours. To the mixture was added ethyl acetate at room temperature, andthe reaction mixture was washed with water and saturated brine, followedby drying over anhydrous magnesium sulfate and concentration underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (18.8g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.27-1.40 (2H, m), 1.47-1.69 (13H, m), 2.64(2H, br t, J=7.5 Hz), 3.27-3.33 (2H, m), 7.32 (2H, d, J=7.7 Hz), 7.82(2H, d, J=7.9 Hz).

E) tert-Butyl 4-[5-(4-bromo-3-methyl-2-nitroanilino)pentyl]benzoate

To a solution of tert-butyl 4-(5-azidopentyl)benzoate (141 mg) intetrahydrofuran (1 ml) and water (1 ml), triphenylphosphine (128 mg) wasadded at room temperature. The mixture was stirred for 4 hours, and thenconcentrated. To a solution of the residue in N,N-dimethylformamide (3ml), potassium carbonate (135 mg) and1-bromo-4-fluoro-2-methyl-3-nitro-benzene (101 mg) were added at roomtemperature, and the reaction mixture was stirred at 80° C. overnight.To the mixture, water was added at 0° C., and the mixture was extractedwith ethyl acetate. The extract solution was washed with saturatedbrine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (189 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.35-1.52 (2H, m), 1.59 (9H, s), 1.61-1.78(4H, m), 2.44 (3H, s), 2.67 (2H, t, J=7.5 Hz), 3.13 (2H, q, J=6.5 Hz),5.68 (1H, br s), 6.52 (1H, d, J=9.1 Hz), 7.21 (2H, d, J=7.9 Hz), 7.46(1H, d, J=9.1 Hz), 7.90 (2H, d, J=8.0 Hz).

F) tert-Butyl 4-[5-(2-amino-4-bromo-3-methylanilino)pentyl]benzoate

A mixture of tert-butyl4-[5-(4-bromo-3-methyl-2-nitro-anilino)pentyl]benzoate (9.27 g),ammonium chloride (5.19 g), iron (5.42 g), ethanol (100 ml), ethylacetate (30 ml), and water (50 ml) was stirred at 85° C. for 4 hours.The mixture was filtered, and the filtrate was concentrated to a halfvolume. To the mixture thus obtained, water was added, and the mixturewas extracted with ethyl acetate. The extract solution was washed withsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (7.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.27-1.69 (15H, m), 2.16 (3H, s), 2.65 (2H,br t, J=7.3 Hz), 2.86-3.14 (2H, m), 4.44-4.71 (3H, m), 6.23 (1H, d,J=8.4 Hz), 6.70 (1H, d, J=8.4 Hz), 7.31 (2H, d, J=7.9 Hz), 7.81 (2H, d,J=7.9 Hz). MS m/z 447.2 [M+H]⁺.

G) tert-Butyl4-[5-(5-bromo-4-methyl-1H-benzotriazol-1-yl)pentyl]benzoate

To a mixture of tert-butyl4-[5-(2-amino-4-bromo-3-methylanilino)pentyl]benzoate (7.4 g) in aceticacid (80 ml), aqueous solution (25 ml) of sodium nitrite (2.28 g) wasadded at room temperature over 1 hour. To the mixture, ice was added,and the mixture was extracted with ethyl acetate. The extract solutionwas washed with water, saturated aqueous sodium bicarbonate solution,and saturated brine, followed by drying over anhydrous magnesium sulfateand concentration under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) and silica gelcolumn chromatography (NH, ethyl acetate/hexane) to give the titlecompound (4.9 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.07-1.28 (2H, m), 1.49-1.65 (11H, m),1.84-1.96 (2H, m), 2.57 (2H, br t, J=7.6 Hz), 2.72 (3H, s), 4.69 (2H, t,J=6.7 Hz), 7.21 (2H, d, J=7.8 Hz), 7.69 (2H, s), 7.75 (2H, d, J=7.9 Hz).MS m/z 458.2 [M+H]⁺.

H) tert-Butyl4-(5-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}pentyl)benzoate

To a solution of tert-butyl4-[5-(5-bromo-4-methyl-1H-benzotriazol-1-yl)pentyl]benzoate (4.8 g),ethyl acrylate (6.85 ml), and N,N-diisopropylethylamine (7.72 mL) inN,N-dimethylformamide (50 ml), tri(o-tolyl)phosphine (0.96 g) andpalladium acetate (353 mg) were added, and the reaction mixture wasstirred at 120° C. for 4 hours under nitrogen atmosphere. Further, tothe reaction mixture, ethyl acrylate (6.9 ml), N,N-diisopropylethylamine(7.72 mL), tri(o-tolyl)phosphine (0.96 g) and palladium acetate (353 mg)were added, and the reaction mixture was stirred at 120° C. for 1 hourunder nitrogen atmosphere. To the mixture thus obtained, water wasadded, and the mixture was extracted with ethyl acetate. The extractsolution was washed with water and saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) and silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (4.84 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.10-1.33 (5H, m), 1.44-1.67 (11H, m),1.85-1.98 (2H, m), 2.58 (2H, br t, J=7.2 Hz), 2.81 (3H, s), 4.22 (2H, q,J=7.2 Hz), 4.69 (2H, br t, J=6.6 Hz), 6.66 (1H, d, J=16.0 Hz), 7.21 (2H,br d, J=7.7 Hz), 7.61-7.78 (3H, m), 7.91-8.14 (2H, m).

MS m/z 478.3 [M+H]⁺.

I) tert-Butyl7-[1-(1-{5-[4-(tert-butoxycarbonyl)phenyl]pentyl}-4-methyl-1H-benzotriazol-5-yl)-3-ethoxy-3-oxopropyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a mixture of tert-butyl4-(5-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}pentyl)benzoate(4.8 g), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(10.8 g), sodium dodecyl sulfate (1.45 g), and triethylamine (4.2 ml) inCPME (100 ml) and water (50 ml), chloro(1,5-cyclooctadiene)rhodium (I)dimer (496 mg) was added. The mixture was stirred at 100° C. for 4 hoursunder argon atmosphere. To the mixture thus obtained, saturated aqueousammonium chloride solution was added, and the mixture was extracted withethyl acetate. The extract solution was washed with saturated brine,followed by drying over anhydrous magnesium sulfate and concentrationunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (6.55g).

¹H NMR (300 MHz, CDCl₃) δ 1.10 (3H, t, J=7.2 Hz), 1.32-1.43 (2H, m),1.47 (9H, s), 1.54-1.60 (9H, m), 1.62-1.76 (2H, m), 1.93-2.03 (2H, m),2.62 (2H, br t, J=7.3 Hz), 2.71-2.79 (2H, m), 2.86 (3H, s), 2.95-3.22(2H, m), 3.49-3.69 (2H, m), 4.02 (2H, q, J=7.0 Hz), 4.45-4.51 (2H, m),4.56 (2H, br t, J=6.8 Hz), 4.88-5.09 (1H, m), 6.89-6.96 (1H, m), 7.03(2H, s), 7.17 (2H, br d, J=7.8 Hz), 7.26 (1H, s), 7.31-7.39 (1H, m),7.88 (2H, d, J=8.0 Hz).

MS m/z 711.5 [M+H]⁺.

J) Ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate

To a solution of tert-butyl7-[1-(1-{5-[4-(tert-butoxycarbonyl)phenyl]pentyl}-4-methyl-1H-benzotriazol-5-yl)-3-ethoxy-3-oxopropyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate(6.55 g) in CPME (10 ml), 4N HCl/CPME solution (70 ml) was added at roomtemperature. The mixture was stirred at room temperature for 2 hours,and then concentrated. To the mixture thus obtained, tetrahydrofuran wasadded, and the mixture was concentrated. A solution of the residue thusobtained and N,N-diisopropylethylamine (9.65 mL) inN,N-dimethylformamide (30 ml) was added dropwise to a solution of HATU(5.25 g) in N,N-dimethylformamide (150 ml) over 1 hour. The mixture wasstirred at room temperature for 3 hours. To the mixture, saturatedaqueous sodium bicarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract solution was washed with waterand saturated brine, followed by drying over anhydrous magnesium sulfateand concentration under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (2.59 g). MS m/z 537.4 [M+H]⁺.

K)[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

To a solution of ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(280 mg) in tetrahydrofuran (4 ml) and ethanol (4 ml), 2N aqueous sodiumhydroxide solution (4 mL) was added, and the reaction mixture wasstirred at room temperature for 3 hours. Under reduced pressure, organicsolvents were removed, and the reaction mixture was then neutralized at0° C. with 2N hydrochloric acid. The precipitate was filtered and washedwith water to give the title compound (265 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76-1.16 (2H, m), 1.35-1.62 (2H, m),1.79-2.21 (2H, m), 2.37-2.73 (5H, m), 2.75-2.90 (2H, m), 2.91-3.21 (2H,m), 3.58-4.23 (4H, m), 4.48-4.91 (3H, m), 5.89 (1H, s), 6.77-7.00 (4H,m), 7.08-7.19 (1H, m), 7.27-7.47 (2H, m), 7.60 (1H, br d, J=8.9 Hz),12.30 (1H, br s).

Example 2[20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 9 or methods equivalent thereto.

Example 3[18-Ethyl-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

A) Methyl 4-bromo-2-ethylbenzoate

To a mixture of 4-bromo-2-fluorobenzoic acid (10.2 g) andtetrahydrofuran (50 ml), an about 1M solution of ethylmagnesium chloridein tetrahydrofuran (140 ml) was added dropwise at 0° C. After stirringthe reaction mixture at 0° C. for 4 hours, 1N hydrochloric acid wasadded at 0° C. Under reduced pressure, organic solvents were removed,and the residue was then extracted with ethyl acetate. The extractsolution was washed with saturated brine, followed by drying overanhydrous magnesium sulfate and concentration under reduced pressure. Toa mixture of the residue and methanol (100 ml), concentrated sulfuricacid (5.00 ml) was added at room temperature, and the reaction mixturewas stirred overnight under heating reflux. The reaction mixture wasconcentrated under reduced pressure, and then extracted with ethylacetate. The extract solution was washed with saturated brine, followedby drying over anhydrous magnesium sulfate and concentration underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (3.26g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (3H, t, J=7.6 Hz), 2.88 (2H, q, J=7.5Hz), 3.83 (3H, s), 7.53 (1H, br d, J=8.6 Hz), 7.57-7.60 (1H, s), 7.71(1H, d, J=8.6 Hz).

B) Methyl 2-ethyl-4-(3-hydroxyprop-1-yn-1-yl)benzoate

To a mixture of methyl 4-bromo-2-ethylbenzoate (3.26 g), 4-pentyn-1-ol(3.74 ml) and triethylamine (35.0 ml),dichlorobis(triphenylphosphine)palladium (II) (0.941 g) and copper (I)iodide (0.255 g) were added at room temperature. Then, the mixture wasdeaerated by repeatedly reducing the pressure and purging nitrogen gas.The mixture was stirred at 70° C. for 3 hours, and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.78g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.14 (3H, t, J=7.5 Hz), 2.88 (2H, q, J=7.6Hz), 3.83 (3H, s), 4.32 (2H, d, J=5.7 Hz), 5.36-5.42 (1H, m), 7.35 (1H,br d, J=7.8 Hz), 7.40 (1H, s), 7.76 (1H, d, J=8.0 Hz).

C) Methyl 2-ethyl-4-(3-hydroxypropyl)benzoate

A mixture of methyl 2-ethyl-4-(3-hydroxyprop-1-yn-1-yl)benzoate (2.78g), 10% palladium/carbon (wetted with ca. 50% water) (1.50 g) andmethanol (50 ml) was stirred under hydrogen atmosphere for 2 hours.Palladium/carbon was removed by filtration, the residue was washed withethyl acetate, and the filtrate was then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.47 g).

MS m/z 223.2 [M+H]⁺.

D) Methyl 2-ethyl-4-(3-oxopropyl)benzoate

To a mixture of methyl 2-ethyl-4-(3-hydroxypropyl)benzoate (1.47 g),triethylamine (4.60 ml) and DMSO (30 ml), sulfur trioxide-pyridinecomplex (3.15 g) was added, and the reaction mixture was then stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was then extracted with ethyl acetate. The extract solutionwas washed with saturated brine, followed by drying over anhydrousmagnesium sulfate and concentration under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (0.420 g).

MS m/z 221.2 [M+H]⁺.

E) Methyl 4-(but-3-en-1-yl)-2-ethylbenzoate

To a mixture of methyltriphenylphosphonium bromide (1.02 g) andtetrahydrofuran (5.00 ml), a 1.6M solution of n-butyllithium in hexane(1.79 ml) was added at 0° C., and the reaction mixture was stirred at 0°C. for 30 minutes. Then, a solution of methyl2-ethyl-4-(3-oxopropyl)benzoate (420 mg) in tetrahydrofuran (5.00 ml)was added at 0° C. After stirring the reaction mixture at 0° C. for 1hour, saturated aqueous ammonium chloride solution was added thereto,and the mixture was extracted with ethyl acetate. The extract solutionwas washed with saturated brine, followed by drying over anhydrousmagnesium sulfate and concentration under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (254 mg).

MS m/z 219.2 [M+H]⁺.

F) 4-(But-3-en-1-yl)-2-ethylbenzoic Acid

To a mixture of methyl 4-(but-3-en-1-yl)-2-ethylbenzoate (254 mg),ethanol (5.00 ml) and tetrahydrofuran (5.00 ml), 1N aqueous sodiumhydroxide solution (5.00 ml) was added at room temperature, and thereaction mixture was stirred at 50° C. overnight. The reaction mixturewas concentrated under reduced pressure. The residue was neutralizedwith 1M hydrochloric acid, and then extracted with ethyl acetate. Theextract solution was washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (187 mg).

MS m/z 205.2 [M+H]⁺.

G)[18-Ethyl-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

The title compound was obtained using 4-(but-3-en-1-yl)-2-ethylbenzoicacid in accordance with the methods shown in Example 9 or methodsequivalent thereto.

Example 4[33-Methyl-2-oxo-7-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

A) Methyl 4-bromo-3-[(prop-2-en-1-yl)oxy]benzoate

A mixture of methyl 4-bromo-3-hydroxybenzoate (5.07 g), potassiumcarbonate (4.55 g), 3-bromoprop-1-ene (2.28 ml) andN,N-dimethylformamide (50 ml) was stirred at 60° C. for 3 hours. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was separated and washed with water andsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (5.93 g).

MS m/z 271.0 [M+H]⁺.

B) Methyl 4-bromo-3-hydroxy-2-(prop-2-en-1-yl)benzoate

A mixture of methyl 4-bromo-3-[(prop-2-en-1-yl)oxy]benzoate (2.06 g) andN-methyl-2-pyrrolidone (12 ml) was stirred at 200° C. for 3 hours undermicrowave irradiation. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer wasseparated and washed with water and saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.38 g).

MS m/z 271.0 [M+H]⁺.

C) Methyl 7-bromo-2-hydroxy-2,3-dihydro-1-benzofuran-4-carboxylate

A mixture of methyl 4-bromo-3-hydroxy-2-(prop-2-en-1-yl)benzoate (1.38g), sodium periodate (2.17 g), microencapsulated osmium tetroxide(7.00%, 923 mg), tetrahydrofuran (25 ml) and water (25 ml) was stirredat room temperature for 6 hours. The reaction mixture was filtered, andthe filtrate was concentrated. Water was added to the residue, and theresidue was extracted with ethyl acetate. The organic layer wasseparated and washed with water and saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (711 mg).

MS m/z 273.0 [M+H]⁺.

D) Methyl 4-bromo-3-hydroxy-2-(2-hydroxyethyl)benzoate

To a mixture of methyl7-bromo-2-hydroxy-2,3-dihydro-1-benzofuran-4-carboxylate (711 mg),tetrahydrofuran (10 ml) and methanol (10 ml), sodium borohydride (98.5mg) was added at 0° C., and the reaction mixture was stirred at the sametemperature for 1 hour. To the reaction mixture, saturated aqueousammonium chloride solution was added at 0° C., and the mixture wasextracted with ethyl acetate. The organic layer was separated and washedwith saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (640 mg).

MS m/z 275.0 [M+H]⁺.

D) Methyl 7-bromo-2,3-dihydro-1-benzofuran-4-carboxylate

To a mixture of methyl 4-bromo-3-hydroxy-2-(2-hydroxyethyl)benzoate (640mg), triphenylphosphine (733 mg) and tetrahydrofuran (20 ml),diisopropyl azodicarboxylate (1.9M toluene solution, 1.47 ml) was addedat room temperature, and the reaction mixture was stirred at 50° C. for5 hours. The reaction mixture was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (590 mg).

MS m/z 257.0 [M+H]⁺.

F) 7-(But-3-en-1-yl)-2,3-dihydro-1-benzofuran-4-carboxylic Acid

The title compound was obtained using methyl7-bromo-2,3-dihydro-1-benzofuran-4-carboxylate in accordance with themethods shown in Example 3 or methods equivalent thereto.

MS m/z 219.2 [M+H]⁺.

G)[33-Methyl-2-oxo-7-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

The title compound was obtained using7-(but-3-en-1-yl)-2,3-dihydro-1-benzofuran-4-carboxylic acid inaccordance with the methods shown in Example 9 or methods equivalentthereto.

Example 5[6,6,33-Trimethyl-2-oxo-7-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

A) Ethyl 3-hydroxy-4-iodobenzoate

A mixture of 3-hydroxy-4-iodobenzoic acid (5.00 g), concentratedsulfuric acid (1.01 ml) and ethanol (50 ml) was stirred at 80° C.overnight. The reaction mixture was concentrated under reduced pressure.To the residue, water and saturated aqueous sodium bicarbonate solutionwere added, and the residue was extracted with ethyl acetate. Theorganic layer was separated and washed with water and saturated brine,followed by drying over anhydrous magnesium sulfate and concentrationunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (4.67g).

MS m/z 293.0 [M+H]⁺.

B) Ethyl 4-iodo-3-[(2-methylprop-2-en-1-yl)oxy]benzoate

A mixture of ethyl 3-hydroxy-4-iodobenzoate (4.67 g), potassiumcarbonate (4.42 g), 3-chloro-2-methylprop-1-ene (2.35 ml) andN,N-dimethylformamide (50 ml) was stirred at 70° C. overnight. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was separated and washed with water andsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (5.48 g).

MS m/z 347.1 [M+H]⁺.

C) Ethyl 7-iodo-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-carboxylate

A mixture of ethyl 4-iodo-3-[(2-methylprop-2-en-1-yl)oxy]benzoate (5.48g) and N-methyl-2-pyrrolidone (50 ml) was stirred at 190° C. overnight.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was separated and washed withwater and saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (1.69 g).

MS m/z 347.1 [M+H]⁺.

D) 7-(But-3-en-1-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-carboxylicAcid

The title compound was obtained using ethyl7-iodo-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-carboxylate in accordancewith the methods shown in Example 3 or methods equivalent thereto.

MS m/z 247.2 [M+H]⁺.

E)[6,6,33-Trimethyl-2-oxo-7-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

The title compound was obtained using7-(but-3-en-1-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-carboxylicacid in accordance with the methods shown in Example 9 or methodsequivalent thereto.

Example 62-[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoicAcid

To a solution of ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate (90 mg) in tetrahydrofuran(2 ml), 1M solution of KHMDS/tetrahydrofuran (0.389 ml) was addeddropwise at −78° C. After stirring the mixture at −78° C. for 45minutes, methyl iodide (0.0242 ml) was added dropwise. While stirringthe mixture, the temperature was raised from −78° C. to 0° C. over anhour. To the reaction solution, saturated aqueous ammonium chloridesolution was added, and the reaction mixture was extracted with ethylacetate. The extract solution was washed with saturated brine, followedby drying over anhydrous magnesium sulfate and concentration underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane).

To a solution of the residue thus obtained in tetrahydrofuran (1 ml) andethanol (1 ml), 2M aqueous sodium hydroxide solution (1 mL) was added,and the reaction mixture was stirred at room temperature overnight. Thereaction solution was neutralized at 0° C. with 2N hydrochloric acid andconcentrated. The residue was purified by preparative HPLC (YMC-ActusTriart C18, mobile phase: water/acetonitrile (0.1% TFA-containingsystem) to give the title compound (4 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76-1.21 (6H, m), 1.37-1.74 (2H, m),1.79-2.22 (2H, m), 2.43 (3H, s), 2.54-2.68 (1H, m), 2.71-2.96 (2H, m),3.09-3.33 (2H, m), 3.87-4.05 (1H, m), 4.08-4.49 (3H, m), 4.52-4.94 (2H,m), 6.26 (1H, br s), 6.76-6.96 (4H, m), 7.02-7.38 (2H, m), 7.47-7.76(2H, m), 12.16 (1H, br s).

Example 7[33-Methyl-2-oxo-5-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(8,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

A) Methyl 4-bromo-2-hydroxy-3-(prop-2-en-1-yl)benzoate

The title compound was obtained using methyl 4-bromo-2-hydroxybenzoatein accordance with the methods shown in Example 4 or methods equivalentthereto.

MS m/z 271.0 [M+H]⁺.

B) Methyl 4-bromo-3-(2,3-dihydroxypropyl)-2-hydroxybenzoate

A mixture of methyl 4-bromo-2-hydroxy-3-(prop-2-en-1-yl)benzoate (1.50g), microencapsulated osmium tetroxide (7.00%, 1.00 g),N-methylmorpholine N-oxide (1.94 g), acetonitrile (10 ml), acetone (10ml) and water (10 ml) was stirred at room temperature overnight. Thereaction mixture was filtered, and the filtrate was concentrated. Waterwas added to the residue, and the residue was extracted with ethylacetate. The organic layer was separated and washed with water andsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.18 g).

MS m/z 305.1 [M+H]⁺.

C) Methyl 4-bromo-2-hydroxy-3-(2-hydroxyethyl)benzoate

To a mixture of methyl 4-bromo-3-(2,3-dihydroxypropyl)-2-hydroxybenzoate(1.18 g), tetrahydrofuran (15 ml) and water (15 ml), sodium periodate(2.49 g) was added at 0° C., and the reaction mixture was stirred atroom temperature for 3 hours. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer wasseparated and washed with water and saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. To a mixture of the residue, tetrahydrofuran (15 ml) andmethanol (15 ml), sodium borohydride (147 mg) was added at 0° C., andthe reaction mixture was stirred at the same temperature for 1 hour. Tothe reaction mixture, saturated aqueous ammonium chloride solution wasadded at 0° C., and the mixture was extracted with ethyl acetate. Theorganic layer was separated and washed with saturated brine, followed bydrying over anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (870 mg).

MS m/z 275.1 [M+H]⁺.

D) Methyl 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylate

The title compound was obtained using methyl4-bromo-2-hydroxy-3-(2-hydroxyethyl)benzoate in accordance with themethods shown in Example 4 or methods equivalent thereto.

MS m/z 257.1 [M+H]⁺.

E) 4-(But-3-en-1-yl)-2,3-dihydro-1-benzofuran-7-carboxylic Acid

The title compound was obtained using methyl4-bromo-2,3-dihydro-1-benzofuran-7-carboxylate in accordance with themethods shown in Example 3 or methods equivalent thereto.

MS m/z 219.2 [M+H]⁺.

F)[33-Methyl-2-oxo-5-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

The title compound was obtained using4-(but-3-en-1-yl)-2,3-dihydro-1-benzofuran-7-carboxylic acid inaccordance with the methods shown in Example 9 or methods equivalentthereto.

Example 8[6,6,33-Trimethyl-2-oxo-5-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

A) Methyl 4-iodo-2-[(2-methylprop-2-en-1-yl)oxy]benzoate

The title compound was obtained using methyl 2-hydroxy-4-iodobenzoate inaccordance with the methods shown in Example 5 or methods equivalentthereto.

MS m/z 333.0 [M+H]⁺.

B) Methyl 2-hydroxy-4-iodo-3-(2-methylprop-2-en-1-yl)benzoate

A mixture of methyl 4-iodo-2-[(2-methylprop-2-en-1-yl)oxy]benzoate (5.93g) and N-methyl-2-pyrrolidone (50 ml) was stirred at 190° C. overnight.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was separated and washed withwater and saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (3.97 g).

MS m/z 333.1 [M+H]⁺.

C) Methyl 4-iodo-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate

A mixture of methyl 2-hydroxy-4-iodo-3-(2-methylprop-2-en-1-yl)benzoate(310 mg) and formic acid (3 ml) was stirred at 100° C. overnight. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (212 mg).

MS m/z 333.0 [M+H]⁺.

D) 4-(But-3-en-1-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylicAcid

The title compound was obtained using methyl4-iodo-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate in accordancewith the methods shown in Example 3 or methods equivalent thereto.

MS m/z 247.2 [M+H]⁺.

E)[6,6,33-Trimethyl-2-oxo-5-oxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

The title compound was obtained using4-(but-3-en-1-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylicacid in accordance with the methods shown in Example 9 or methodsequivalent thereto.

Example 9[18-Chloro-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

A) tert-Butyl (4-bromo-3-methyl-2-nitrophenyl)carbamate

To a mixture of 4-bromo-3-methyl-2-nitro-aniline (2 g) and di-tert-butyldicarbonate (3.97 g) in tetrahydrofuran (20 ml),N,N-dimethyl-4-aminopyridine (106 mg) was added, and the reactionmixture was stirred at room temperature for 3 days. After concentratingthe reaction solution, tetrahydrofuran (20 ml) was added, 2M aqueoussodium hydroxide solution (5.2 ml) was added, and the reaction mixturewas stirred at 70° C. overnight. Water was added to the mixture thusobtained, and the mixture was extracted with diisopropyl ether. Theextract solution was washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (2.13 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (9H, s), 2.30 (3H, s), 7.32 (1H, d,J=8.9 Hz), 7.82 (1H, d, J=8.8 Hz), 9.35 (1H, s).

B) tert-Butyl(4-bromo-3-methyl-2-nitrophenyl)(2E)-but-2-en-1-ylcarbamate

To a solution of 4-bromo-3-methyl-2-nitro-aniline (8.5 g) anddi-tert-butyl dicarbonate (17.7 ml) in tetrahydrofuran (80 ml),N,N-dimethyl-4-aminopyridine (900 mg) was added, and the reactionmixture was stirred at room temperature overnight. To the reactionsolution, 2M aqueous sodium hydroxide solution (37 ml) was added, andthe reaction mixture was stirred at 70° C. overnight. Water was added tothe mixture thus obtained, and the mixture was extracted with diethylether. The extract solution was washed with saturated brine, followed bydrying over anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give Boc-form (11.4 g).

To a solution of the Boc-form (10 g) in N,N-dimethylformamide (70 ml),sodium hydride (50%, 1.59 g) was added at 0° C. After stirring thereaction mixture at 0° C. for 30 minutes, crotyl bromide (4.48 g) wasadded at 0° C. After stirring the mixture at room temperature for 4hours, further crotyl bromide (4.48 g) was added at 0° C. The reactionmixture was stirred at room temperature overnight. To the mixture,saturated aqueous ammonium chloride solution was added at 0° C., and themixture was extracted with ethyl acetate. The organic layer wasseparated and washed with water and saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (7 g).

¹H NMR (300 MHz, CDCl₃) δ 1.37 (9H, br s), 1.66 (3H, br s), 2.37 (3H,s), 3.43-4.00 (1H, m), 4.15-4.61 (1H, m), 5.41-5.71 (2H, m), 6.97 (1H,br d, J=7.7 Hz), 7.64 (1H, d, J=8.5 Hz).

C) 4-Bromo-N-[(2E)-but-2-en-1-yl]-3-methyl-2-nitroaniline

To a mixture of tert-butyl(4-bromo-3-methyl-2-nitrophenyl)(2E)-but-2-en-1-ylcarbamate (7 g) inethyl acetate (10 ml), 4N HCl/ethyl acetate solution (30 ml) was addedat room temperature. The mixture was stirred at room temperatureovernight, and concentrated. To the residue thus obtained, saturatedaqueous sodium bicarbonate solution was added, and the mixture wasextracted with ethyl acetate. The organic layer was separated and washedwith saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure, to give the titlecompound (4.9 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.58-1.74 (3H, m), 2.24 (3H, s), 3.61-3.87(2H, m), 5.24-5.72 (2H, m), 6.24-6.43 (1H, m), 6.55-6.74 (1H, m),7.45-7.65 (1H, m).

D) 4-Bromo-N-1-[(2E)-but-2-en-1-yl]-3-methylbenzene-1,2-diamine

A mixture of 4-bromo-N-[(2E)-but-2-en-1-yl]-3-methyl-2-nitroaniline (4.9g), ammonium chloride (9.19 g) and iron (4.8 g) in ethanol (50 ml) andwater (10 ml) was stirred at 85° C. for 6 hours. The mixture wasfiltered, saturated aqueous sodium bicarbonate solution was added to thefiltrate, and the mixture was extracted with ethyl acetate. The extractsolution was washed with saturated brine, followed by drying overanhydrous magnesium sulfate and concentration under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (3.8 g).

¹H NMR (300 MHz, CDCl₃) δ 1.72 (3H, br d, J=5.9 Hz), 2.31 (3H, s),3.02-3.31 (1H, m), 3.35-3.58 (2H, m), 3.59-3.78 (2H, m), 5.53-5.89 (2H,m), 6.45 (1H, d, J=8.5 Hz), 7.00 (1H, d, J=8.5 Hz).

E) Ethyl(2E)-3-[1-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate(E/Z isomer Mixture)

To a mixture of4-bromo-N-1-[(2E)-but-2-en-1-yl]-3-methylbenzene-1,2-diamine (3.6 g) in6M hydrochloric acid (38 ml), a solution of sodium nitrite (2.06 g) inwater (4 ml) was slowly added at 0° C. The mixture was stirred at roomtemperature for 2 hours. To the reaction solution, 2M aqueous sodiumhydroxide solution was added at 0° C., and the mixture was extractedwith ethyl acetate. The extract solution was washed with saturatedbrine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give cyclized form(3.2 g).

To a solution of the cyclized form (3.13 g), ethyl acrylate (7.7 ml) andN,N-diisopropylethylamine (8.11 mL) in N,N-dimethylformamide (14 ml),tri(o-tolyl)phosphine (1.07 g) and palladium acetate (396 mg) wereadded, and the reaction mixture was stirred at 120° C. for 6 hours.Further, after cooling the reaction mixture to room temperature, waterwas added thereto, and the mixture was extracted with ethyl acetate. Theextract solution was washed with water and saturated brine, followed bydrying over anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (3.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (3H, t, J=7.1 Hz), 1.62-1.98 (3H, m),2.81 (3H, s), 4.22 (2H, q, J=7.1 Hz), 5.22-5.44 (2H, m), 5.56-5.94 (2H,m), 6.65 (1H, d, J=15.9 Hz), 7.58-7.72 (1H, m), 7.87-8.19 (2H, m).

MS m/z 286.2 [M+H]⁺.

F) tert-Butyl7-{1-[1-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate(E/Z isomer mixture)

To a mixture of ethyl(2E)-3-[1-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate(E/Z isomer mixture) (3.1 g), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(5.85 g), sodium dodecyl sulfate (1.57 g), and triethylamine (4.54 ml)in CPME (50 ml) and water (25 ml), chloro(1,5-cyclooctadiene)rhodium (I)dimer (536 mg) was added at room temperature. The mixture was stirred at90° C. for 4 hours under nitrogen atmosphere. Water was added to themixture thus obtained, and the mixture was extracted with ethyl acetate.The extract solution was washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (4.27 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.01 (3H, br t, J=7.0 Hz), 1.41 (9H, s),1.59-1.88 (3H, m), 2.68 (2H, br t, J=5.7 Hz), 2.77 (3H, s), 3.16 (2H, brd, J=7.6 Hz), 3.49 (2H, br t, J=5.4 Hz), 3.93 (2H, q, J=7.0 Hz), 4.43(2H, br s), 4.82 (1H, br t, J=7.8 Hz), 5.14-5.41 (2H, m), 5.50-5.93 (2H,m), 6.96-7.24 (3H, m), 7.53 (2H, q, J=8.5 Hz).

MS m/z 519.4 [M+H]⁺.

G) Ethyl3-[1-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]-3-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanoate(E/Z isomer Mixture)

To a mixture of tert-butyl7-{1-[1-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate(E/Z isomer mixture) (4.2 g) in ethyl acetate (5 ml), 4N HCl/ethylacetate solution (40 ml) was added, and the reaction mixture was stirredat room temperature for 5 hours. The mixture was concentrated, and tothe residue thus obtained, saturated aqueous sodium bicarbonate solutionwas added, and the mixture was extracted with ethyl acetate. The organiclayer was separated and washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (2.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.01 (3H, t, J=6.8 Hz), 1.53-1.87 (3H, m),2.22-2.43 (1H, m), 2.54-2.61 (2H, m), 2.75 (3H, s), 2.87 (2H, br t,J=5.3 Hz), 3.12 (2H, br d, J=7.6 Hz), 3.74 (2H, s), 3.93 (2H, q, J=7.1Hz), 4.79 (1H, br t, J=7.7 Hz), 5.13-5.40 (2H, m), 5.54-5.90 (2H, m),6.81-7.11 (3H, m), 7.35-7.67 (2H, m).

H) tert-Butyl 2-chloro-4-(3-hydroxyprop-1-yn-1-yl)benzoate

tert-Butyl 4-bromo-2-chlorobenzoate (3.67 g), 2-propyn-1-ol (2.117 g),copper (I) iodide (120 mg), triethylamine (3.54 ml), andbis(triphenylphosphine)palladium (II) dichloride (442 mg) were suspendedin DMF (30 ml), and the reaction mixture was stirred at 80° C. for 8hours under nitrogen atmosphere. The reaction solution was diluted withethyl acetate and washed with saturated brine, followed by drying overanhydrous sodium sulfate and concentration under reduced pressure. Theresidue was purified by silica gel chromatography (ethyl acetate/hexane)to give the title compound (1.85 g).

¹H NMR (300 MHz, CDCl₃) δ 1.60 (9H, s), 4.51 (2H, d, J=6.1 Hz),7.30-7.36 (1H, m), 7.45-7.50 (1H, m), 7.68 (1H, d, J=8.0 Hz).

I) tert-Butyl 2-chloro-4-(3-hydroxypropyl)benzoate

tert-Butyl 2-chloro-4-(3-hydroxyprop-1-yn-1-yl)benzoate (1.2 g) andtris(triphenylphosphine)rhodium (I) chloride (208 mg) were dissolved intoluene (100 mL), and the reaction mixture was stirred at 60° C. for 20hours under hydrogen atmosphere. The reaction solution was cooled andthen concentrated under reduced pressure, and the residue product thusobtained was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (1.047 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.54 (9H, s), 1.64-1.78 (2H, m), 2.65 (2H,br t, J=7.7 Hz), 3.39 (2H, q, J=5.9 Hz), 4.51 (1H, t, J=5.0 Hz), 7.26(1H, d, J=8.0 Hz), 7.38 (1H, s), 7.60-7.67 (1H, m).

J) tert-Butyl 2-chloro-4-(3-oxopropyl)benzoate

A solution of tert-butyl 2-chloro-4-(3-hydroxypropyl)benzoate (600 mg)and triethylamine (2.49 ml) in DMSO (30 ml) was cooled to 0° C., sulfurtrioxide-pyridine complex (1.764 g) was added in several portions, andthe reaction mixture was stirred at room temperature for 15 hours. Thereaction solution was diluted with ethyl acetate, and then washed withwater. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, and the residue product thusobtained was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (476 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.60 (9H, s), 2.75-2.84 (2H, m), 2.90-3.01(2H, m), 7.12 (1H, d, J=8.0 Hz), 7.26 (1H, s), 7.68 (1H, d, J=8.0 Hz),9.81 (1H, s).

K) tert-Butyl 4-(but-3-en-1-yl)-2-chlorobenzoate

A suspension of methyltriphenylphosphonium bromide (2924 mg) in THF (30ml) was cooled to 0° C., and potassium tert-butoxide (835 mg) was addedin several portions. After raising the temperature of the reactionsolution to room temperature, the solution was stirred for further 1hour. The reaction solution was cooled to 0° C. again, and a solution oftert-butyl 2-chloro-4-(3-oxopropyl)benzoate (400 mg) in THF (1 ml) wasadded dropwise thereto. The temperature of the reaction mixture wasraised to room temperature, and the mixture was then stirred for 15hours. The reaction solution was poured into saturated aqueous ammoniumchloride solution, and the reaction mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The residue product thus obtained was purified by silica gelchromatography (ethyl acetate/hexane) to give the title compound (270mg).

¹H NMR (300 MHz, CDCl₃) δ 1.55-1.66 (9H, m), 2.25-2.45 (2H, m),2.61-2.77 (2H, m), 4.90-5.11 (2H, m), 5.68-5.90 (1H, m), 7.10 (1H, d,J=7.9 Hz), 7.33 (1H, s), 7.68 (1H, d, J=7.9 Hz).

L) 4-(But-3-en-1-yl)-2-chlorobenzoic Acid

To a solution of tert-butyl 4-(but-3-en-1-yl)-2-chlorobenzoate (200 mg)in toluene (2.0 ml), trifluoroacetic acid (2.0 ml) was added dropwise atroom temperature. The reaction solution was stirred at the sametemperature for 2 hours, and then concentrated under reduced pressure togive the title compound (150 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.27-2.41 (2H, m), 2.72 (2H, t, J=7.6 Hz),4.93-5.08 (2H, m), 5.70-5.91 (1H, m), 7.27 (1H, d, J=7.9 Hz), 7.41 (1H,s), 7.72 (1H, d, J=7.9 Hz), 13.02-13.34 (1H, m).

M) Ethyl3-{2-[4-(but-3-en-1-yl)-2-chlorobenzoyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-{1-[(2E)-but-2-en-1-yl]-4-methyl-1H-benzotriazol-5-yl}propanoate

To a solution of ethyl3-[1-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]-3-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanoate(E/Z isomer mixture) (25 mg), 4-(but-3-en-1-yl)-2-chlorobenzoic acid(18.5 mg), anhydrous 1-hydroxybenzotriazole (16.1 mg) and triethylamine(0.025 ml) in DMF (1 ml),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (18.5 mg) was added, andthe reaction mixture was stirred at room temperature for 15 hours. Thereaction solution was diluted with ethyl acetate, and then washed withsaturated brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure, and the crude productthus obtained was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (30 mg).

MS m/z 611.3 [M+H]⁺.

N) Ethyl[(12Z)-18-chloro-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,12,16,18,24,27,30-undecaen-2-yl]acetate

Ethyl3-{2-[4-(but-3-en-1-yl)-2-chlorobenzoyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-{1-[(2E)-but-2-en-1-yl]-4-methyl-1H-benzotriazol-5-yl}propanoate(30 mg) was dissolved in 1,2-dichloroethane (35 ml),(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium(6.15 mg) was added, and the reaction mixture was stirred at 50° C. for15 hours. The reaction solution was concentrated under reduced pressure,and the crude product thus obtained was purified by silica gelchromatography (ethyl acetate/hexane) to give the title compound (15mg).

MS m/z 569.3 [M+H]⁺.

O)[18-Chloro-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Ethyl[(12Z)-18-chloro-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,12,16,18,24,27,30-undecaen-2-yl]acetate(33 mg) and tris(triphenylphosphine)rhodium (I) chloride (3.0 mg) weredissolved in toluene (10 ml), and the reaction mixture was stirred at60° C. for 20 hours under hydrogen atmosphere, and then concentratedunder reduced pressure. The residue was purified by silica gelchromatography (ethyl acetate/hexane). The crude product thus obtainedwas dissolved in a mixture of ethanol (1 ml) and THF (1 ml), 2M aqueoussodium hydroxide solution (1 ml) was added, and the reaction mixture wasstirred at room temperature for 1 hour. To the reaction solution, 1M HCl(2.1 ml) was added to acidify the solution, and the mixture was thenextracted with ethyl acetate. The extract solution was dried overanhydrous magnesium sulfate and then concentrated under reduced pressureto give the title compound (12.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.29-1.68 (2H, m), 1.88-2.14 (2H, in), 2.45(3H, m), 2.85 (2H, m), 2.90-3.17 (3H, m), 3.57-3.77 (3H, m), 3.80-4.07(3H, m), 4.60-4.89 (4H, m), 5.68-5.90 (1H, m), 6.56 (2H, m), 6.91-7.07(1H, m), 7.11-7.23 (1H, m), 7.25-7.44 (2H, m), 7.55-7.66 (1H, m),12.12-12.34 (1H, m).

Example 10[18-Fluoro-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

A) 4-(But-3-en-1-yl)-2-fluorobenzoic Acid

The title compound was obtained by subjecting tert-butyl4-bromo-2-fluoro-benzoate to the same operation as Example 9.

¹H NMR (300 MHz, DMSO-d₆) δ 2.24-2.43 (2H, m), 2.67-2.81 (2H, m),4.87-5.13 (2H, m), 5.82 (1H, ddt, J=16.7, 10.1, 6.5 Hz), 7.06-7.25 (2H,m), 7.78 (1H, br t, J=8.0 Hz), 13.08 (1H, br s).

B)[18-Fluoro-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

The title compound was obtained by subjecting4-(but-3-en-1-yl)-2-fluorobenzoic acid to the same operation as Example9.

Example 11[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid <Chiral, Synthesis from chiral ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

A) Ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, Retention Time Long)

Racemate of ethyl2-(32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3,5,7(32),8,16(31),17,19(30),24,27-decaen-2-yl]acetate(2.59 g) was fractionated by preparative supercritical CO₂chromatography system (column: Cellulose-C (5 μm) 250×30 mm I.D., mobilephase: carbon dioxide/methanol=65/35). The fraction thus obtained wasconcentrated under reduced pressure to give the title compound (1.22 g)(chiral, retention time long).

Analysis conditions retention time: 4.997 minutes (column: Alcyon SFCCSP Cellulose-C (5 μm), 250×4.6 mm mobile phase: carbondioxide/methanol=65/35, flow rate: 3.0 mL/min, temperature: 35° C.,detection: UV 210 nm, sample concentration: 1 mg/mL, injection volume:0.005 mL).

B) Ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, Retention Time Short)

Racemate of ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(2.59 g) was fractionated by preparative supercritical CO₂chromatography system (column: Cellulose-C (5 μm) 250×30 mm I.D., mobilephase: carbon dioxide/methanol=65/35). The fraction thus obtained wasconcentrated under reduced pressure to give the title compound (1.23 g)(chiral, retention time short).

Analysis conditionsretention time: 3.795 minutes (column: Alcyon SFC CSPCellulose-C (5 μm), 250×4.6 mm I.D., mobile phase: carbondioxide/methanol=65/35, flow rate: 3.0 mL/min, temperature: 35° C.,detection: UV 210 nm, sample concentration: 1 mg/mL, injection volume:0.005 mL).

C)[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid <Chiral, synthesis from chiral ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

To a solution of ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, retention time short) (1.23 g) in tetrahydrofuran (12 ml) andethanol (6 ml), 1N aqueous sodium hydroxide solution (11.5 mL) wasadded, and the reaction mixture was stirred at room temperature for 6hours. The reaction solution was concentrated to remove organicsolvents. Subsequently, the solution was diluted with water, and thenmade slightly acidic (pH4-7) with 1N hydrochloric acid at 0° C. Theprecipitate was filtered and washed with water to give the titlecompound (1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.70-1.12 (2H, m), 1.30-1.66 (2H, m),1.80-2.21 (2H, m), 2.50 (5H, br s), 2.75-2.88 (2H, m), 2.91-3.18 (2H,m), 3.57-4.20 (4H, m), 4.55-4.89 (3H, m), 5.89 (1H, s), 6.80-6.94 (4H,m), 7.14 (1H, br d, J=7.0 Hz), 7.27-7.45 (2H, m), 7.60 (1H, d, J=9.1Hz), 12.25 (1H, s).

Analysis conditionsretention time: 19.0 minutes (column: DAICELCHIRALPAK IB N-5 (5 μm), 250×4.6 mm I.D., mobile phase: A/B=82.5/17.5,A=hexane (0.1% trifluoroacetic acid), B=ethanol (0.1% trifluoroaceticacid), measurement temperature: room temperature, flow rate: 2.0 mL/min,detection: UV 220 nm and 254 nm, sample concentration: 0.5 mg/mL,injection volume: 0.01 mL).

Example 12[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid <Chiral, Synthesis from chiral ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Long)>

To a solution of ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, retention time long) (1.22 g) in tetrahydrofuran (12 ml) andethanol (6 ml), 1M aqueous sodium hydroxide solution (11 mL) was added,and the reaction mixture was stirred at room temperature for 6 hours.The reaction solution was concentrated to remove organic solvents.Subsequently, the solution was diluted with water, and made slightlyacidic (pH4-7) with 1N hydrochloric acid at 0° C. The precipitate wasfiltered and washed with water to give the title compound (1.12 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.72-1.09 (2H, m), 1.38-1.64 (2H, m),1.71-2.25 (2H, m), 2.42-2.63 (5H, m), 2.83 (2H, br t, J=6.1 Hz),2.92-3.20 (2H, m), 3.67 (1H, dt, J=13.0, 6.4 Hz), 3.81-4.24 (3H, m),4.42-5.07 (3H, m), 5.89 (1H, s), 6.77-6.98 (4H, m), 7.14 (1H, d, J=7.9Hz), 7.28-7.47 (2H, m), 7.61 (1H, d, J=8.6 Hz), 12.21 (1H, br s).

Analysis conditionsretention time: 29.9 minutes (column: DAICELCHIRALPAK IB N-5 (5 μm), 250×4.6 mm I.D., mobile phase: A/B=82.5/17.5,A=hexane (0.1% trifluoroacetic acid), B=ethanol (0.1% trifluoroaceticacid), measurement temperature: room temperature, flow rate: 2.0 mL/min,detection: UV 220 nm and 254 nm, sample concentration: 0.5 mg/mL,injection volume: 0.01 mL).

Example 13[31-Methyl-19-oxo-8,9,10,20-tetraazahexacyclo[18.5.3.2^(15,18).1^(3,7).0^(6,10).0^(23,27)]hentriaconta-1(25),3(31),4,6,8,15,17,23,26,29-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 9 or methods equivalent thereto.

Example 14[(13Z)-33-Methyl-21-oxo-8,9,10,22-tetraazahexacyclo[20.5.3.2^(17,20).1^(3,7).0^(6,10).0^(25,29)]tritriaconta-1(27),3(33),4,6,8,13,17,19,25,28,31-undecaen-2-yl]aceticAcid

A) tert-Butyl but-3-en-1-yl(3-methyl-2-nitrophenyl)carbamate

To a solution of tert-butyl N-(3-methyl-2-nitro-phenyl)carbamate (7 g)in N,N-dimethylformamide (70 ml), sodium hydride (50%, 1.33 g) was addedat 0° C. After stirring the reaction mixture at 0° C. for 20 minutes,4-bromo-1-butene (3.75 g) was added at 0° C. After stirring the mixtureat room temperature for 4 hours, further 4-bromo-1-butene (3.75 g) wasadded at 0° C. The reaction mixture was stirred at 60° C. overnight. Tothe mixture, saturated aqueous ammonium chloride solution was added at0° C., and the mixture was extracted with ethyl acetate. The organiclayer was separated and washed with water and saturated brine, followedby drying over anhydrous magnesium sulfate and concentration underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (4.33g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (9H, br s), 2.14-2.38 (5H, s),3.25-3.85 (2H, m), 4.92-5.19 (2H, m), 5.65-5.87 (1H, m), 7.29-7.48 (2H,m), 7.49-7.60 (1H, m).

B) 4-Bromo-N-(but-3-en-1-yl)-3-methyl-2-nitroaniline

To a mixture of tert-butylbut-3-en-1-yl(3-methyl-2-nitrophenyl)carbamate (4.33 g) in ethyl acetate(10 ml), 4N HCl/ethyl acetate solution (40 ml) was added at 0° C. Themixture was stirred at 0° C. for 20 minutes, stirred at room temperatureovernight, and then concentrated. To the residue thus obtained,saturated aqueous sodium bicarbonate solution was added, and the mixturewas extracted with ethyl acetate. The organic layer was separated andwashed with saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure.

To a solution of the residue thus obtained in N,N-dimethylformamide (25ml), N-bromosuccinimide (2.5 g) was added at 0° C. After stirring thereaction solution at room temperature overnight, water was added theretoat 0° C., and the mixture was extracted with ethyl acetate. The organiclayer was separated and washed with water and saturated brine, followedby drying over anhydrous magnesium sulfate and concentration underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (3.38g).

¹ NMR (300 MHz, DMSO-d₆) δ 2.18-2.36 (5H, m), 3.20 (2H, q, J=6.6 Hz),4.92-5.16 (2H, m), 5.81 (1H, ddt, J=17.1, 10.3, 6.6 Hz), 6.09 (1H, br t,J=5.3 Hz), 6.76 (1H, d, J=9.1 Hz), 7.55 (1H, d, J=9.1 Hz). MS m/z 285.0[M+H]⁺.

C) Ethyl(2E)-3-[1-(but-3-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate

To a mixture of 4-bromo-N-(but-3-en-1-yl)-3-methyl-2-nitroaniline (3.18g) in ethanol (40 ml), tin chloride dihydrate (2.53 g) was added. Afterstirring the mixture at 90° C. for 3 hours, further tin chloridedihydrate (2.53 g) was added. The reaction mixture was stirred at 90° C.for 3 hours, and then concentrated. To the residue thus obtained, icewas added. Further, 1M sodium hydroxide was added to the mixture forneutralization, and the mixture was then extracted with ethyl acetate.The organic layer was separated and washed with saturated brine,followed by drying over anhydrous magnesium sulfate and concentrationunder reduced pressure. The residue thus obtained was purified by silicagel column chromatography (ethyl acetate/hexane).

To a mixture of the residue thus obtained (1.6 g) in 6M hydrochloricacid (16 ml), a solution of sodium nitrite (865 mg) in water (2 ml) wasslowly added at 0° C. The mixture was stirred at room temperatureovernight. To the reaction solution, 2M aqueous sodium hydroxidesolution was added, and the mixture was extracted with ethyl acetate.The extract solution was washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give benzotriazole derivative (1.23 g).

To a solution of the benzotriazole derivative (1.23 g), ethyl acrylate(2.78 g), N,N-diisopropylethylamine (2.39 g) and tri(o-tolyl)phosphine(422 mg) in N,N-dimethylformamide (20 ml), palladium acetate (156 mg)was added, and the reaction mixture was stirred at 120° C. for 4 hoursunder microwave irradiation. After cooling the reaction mixture to roomtemperature, water and ethyl acetate were added thereto, and theinsoluble material was filtered. Water was added to the filtrate, andthe mixture was extracted with ethyl acetate. The extract solution waswashed with water and saturated brine, followed by drying over anhydrousmagnesium sulfate and concentration under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (490 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (3H, t, J=7.1 Hz), 2.68 (2H, q, J=6.7Hz), 2.80 (3H, s), 4.22 (2H, q, J=7.1 Hz), 4.78 (2H, t, J=6.8 Hz),4.89-5.09 (2H, m), 5.79 (1H, ddt, J=17.1, 10.1, 6.8 Hz), 6.65 (1H, d,J=15.9 Hz), 7.74 (1H, d, J=8.7 Hz), 7.90-8.09 (2H, m). MS m/z 286.2[M+H]⁺.

D) Ethyl[(13Z)-33-methyl-21-oxo-8,9,10,22-tetraazahexacyclo[20.5.3.2^(17,20).1^(3,7).0^(6,10).0^(25,29)]tritriaconta-1(27),3(33),4,6,8,13,17,19,25,28,31-undecaen-2-yl]acetate

Synthesis was carried out using ethyl(2E)-3-[1-(but-3-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate inaccordance with the methods shown in Example 9 or methods equivalentthereto.

E)[(13Z)-33-Methyl-21-oxo-8,9,10,22-tetraazahexacyclo[20.5.3.2^(17,20).1^(3,7).0^(6,10).0^(25,29)]tritriaconta-1(27),3(33),4,6,8,13,17,19,25,28,31-undecaen-2-yl]aceticAcid

To a solution of ethyl[(13Z)-33-methyl-21-oxo-8,9,10,22-tetraazahexacyclo[20.5.3.2^(17,20).1^(3,7).0^(6,10).0^(25,29)]tritriaconta-1(27),3(33),4,6,8,13,17,19,25,28,31-undecaen-2-yl]acetate(40 mg) in tetrahydrofuran (1 ml) and ethanol (1 ml), 2M aqueous sodiumhydroxide solution (2 mL) was added, and the reaction mixture wasstirred at room temperature overnight. The reaction solution wasconcentrated to remove organic solvents, and then neutralized with 1Nhydrochloric acid at 0° C. The precipitate was filtered and washed withwater to give the title compound (30 mg).

Example 15[33-Methyl-21-oxo-8,9,10,22-tetraazahexacyclo[20.5.3.2^(17,20).1^(3,7).0^(6,10).0^(25,29)]tritriaconta-1(27),3(33),4,6,8,17,19,25,28,31-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 9 or 14, or methods equivalent thereto.

Example 16[32-Methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

A) 3-(4-Bromo-3-methyl-2-nitroanilino)propan-1-ol

To a solution of 1-bromo-4-fluoro-2-methyl-3-nitro-benzene (2 g) inN,N-dimethylformamide (15 ml), potassium carbonate (2.36 g) and3-amino-1-propanol (0.83 g) were added at room temperature, and thereaction mixture was stirred at 80° C. overnight. Water (80 ml) wasadded to the mixture at 0° C. The precipitate was separated byfiltration, and then washed with water to give the title compound (2.4g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.67 (2H, quin, J=6.3 Hz), 2.25 (3H, s),3.19 (2H, q, J=6.1 Hz), 3.47 (2H, q, J=5.5 Hz), 4.59 (1H, t, J=4.9 Hz),6.08-6.35 (1H, m), 6.74 (1H, d, J=9.2 Hz), 7.54 (1H, d, J=9.1 Hz).

B) 3-(2-Amino-4-bromo-3-methylanilino)propan-1-ol

A mixture of 3-(4-bromo-3-methyl-2-nitroanilino)propan-1-ol (7.53 g),ammonium chloride (13.9 g), iron (7.27 g), ethanol (54 ml) and water (20ml) was stirred at 85° C. overnight. The mixture was filtered, and thefiltrate was concentrated. To the mixture thus obtained, saturatedaqueous sodium bicarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract solution was washed withsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was washed with ethylacetate to give the title compound. The washing liquid was concentrated,and the residue thus obtained was purified by silica gel columnchromatography (ethyl acetate/hexane) to further give the titlecompound. In total, 4.8 g of the title compound was obtained.

¹H NMR (300 MHz, DMSO-d₆) δ 1.73 (2H, quin, J=6.6 Hz), 2.16 (3H, s),3.04 (2H, q, J=6.5 Hz), 3.51 (2H, q, J=5.6 Hz), 4.40-4.67 (4H, m), 6.25(1H, d, J=8.6 Hz), 6.71 (1H, d, J=8.5 Hz).

C) 3-(5-Bromo-4-methyl-1H-benzotriazol-1-yl)propan-1-ol

To a mixture of 3-(2-amino-4-bromo-3-methylanilino)propan-1-ol (4.8 g)in 6N hydrochloric acid (45 ml), a solution of sodium nitrite (2.56 g)in water (10 ml) was slowly added at 0° C. The mixture was stirred atroom temperature for 2 hours. To the reaction solution, 4N aqueoussodium hydroxide solution was added at 0° C. for neutralization, and themixture was extracted with ethyl acetate. The extract solution waswashed with saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (4 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.04 (2H, quin, J=6.4 Hz), 2.72 (3H, s),3.39 (2H, q, J=5.5 Hz), 4.67 (1H, br t, J=4.7 Hz), 4.74 (2H, t, J=6.9Hz), 7.69 (2H, s).

MS m/z 270.1 [M+H]⁺.

D) tert-Butyl4-{[3-(5-bromo-4-methyl-1H-benzotriazol-1-yl)propoxy]methyl}benzoate

To a solution of 3-(5-bromo-4-methyl-1H-benzotriazol-1-yl)propan-1-ol(6.55 g) in N,N-dimethylformamide (100 ml), sodium hydride (oily, 50%,1.51 g) was added at 0° C. under nitrogen atmosphere. After stirring thereaction mixture at 0° C. for 30 minutes, tert-butyl4-(bromomethyl)benzoate (7.23 g) was added at 0° C. After stirring themixture at room temperature for 2 hours, saturated aqueous ammoniumchloride solution was added thereto, and the mixture was extracted withethyl acetate. The organic layer was separated and washed with saturatedbrine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (8.61 g).

¹ H NMR (300 MHz, DMSO-d₆) δ 1.55 (9H, s), 2.21 (2H, quin, J=6.1 Hz),2.69 (3H, s), 3.43 (2H, br t, J=5.6 Hz), 4.43 (2H, s), 4.79 (2H, t,J=6.5 Hz), 7.26 (2H, br d, J=7.8 Hz), 7.66 (2H, s), 7.81 (2H, d, J=7.8Hz).

MS m/z 460.2 [M+H]⁺.

E) tert-Butyl4-[(3-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}propoxy)methyl]benzoate

To a solution of tert-butyl4-{[3-(5-bromo-4-methyl-1H-benzotriazol-1-yl)propoxy]methyl}benzoate (9g), ethyl acrylate (11.7 g) and N,N-diisopropylethylamine (13.5 ml) inN,N-dimethylformamide (200 ml), tri(o-tolyl)phosphine (1.79 g) andpalladium acetate (658 mg) were added, and the reaction mixture wasstirred at 120° C. for 4 hours under argon atmosphere. The reactionmixture was concentrated, water was added thereto, and the mixture wasextracted with ethyl acetate. The extract solution was washed with waterand saturated brine, followed by drying over anhydrous magnesium sulfateand concentration under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (7.9 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (3H, t, J=7.2 Hz), 1.54 (9H, s),2.10-2.32 (2H, m), 2.79 (3H, s), 3.43 (2H, br t, J=5.5 Hz), 4.22 (2H, q,J=7.0 Hz), 4.44 (2H, s), 4.79 (2H, br t, J=6.4 Hz), 6.64 (1H, d, J=15.8Hz), 7.28 (2H, d, J=7.9 Hz), 7.59-7.84 (3H, m), 7.87-8.14 (2H, m).

F) tert-Butyl7-{1-[1-(3-{[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a mixture of tert-butyl4-[(3-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}propoxy)methyl]benzoate(6.88 g), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(15.5 g), sodium dodecyl sulfate (2.07 g), triethylamine (6 ml), CPME(200 ml) and water (100 ml), chloro(1,5-cyclooctadiene)rhodium (I) dimer(707 mg) was added at room temperature. The mixture was stirred at 100°C. for 3 hours under argon atmosphere. To the mixture thus obtained,saturated aqueous ammonium chloride solution was added, and the mixturewas extracted with ethyl acetate. The extract solution was washed withsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (10.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.00 (3H, t, J=7.0 Hz), 1.40 (9H, s), 1.54(9H, s), 2.06-2.32 (2H, m), 2.63-2.72 (2H, m), 2.77 (3H, s), 3.06-3.20(2H, m), 3.37-3.55 (4H, m), 3.92 (2H, q, J=7.0 Hz), 4.36-4.50 (4H, m),4.73 (2H, br t, J=6.3 Hz), 4.76-5.00 (1H, m), 6.99-7.20 (3H, m), 7.33(2H, br d, J=7.7 Hz), 7.42-7.65 (2H, m), 7.83 (2H, d, J=7.7 Hz).

MS m/z 713.4 [M+H]⁺.

G) Ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate

To a solution of tert-Butyl7-{1-[1-(3-{[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate(6.55 g) in CPME (10 ml), 4N HCl/CPME solution (69 ml) was added at roomtemperature. The mixture was stirred at room temperature for 2 hours,and then concentrated. To the mixture thus obtained, tetrahydrofuran wasadded, and the mixture was concentrated. To a solution of the residuethus obtained in N,N-dimethylformamide (50 ml),N,N-diisopropylethylamine (8.35 ml) was added at 0° C. The solution thusobtained was slowly added dropwise to a solution of HATU (4.55 g) inN,N-dimethylformamide (350 ml) at room temperature. The mixture wasstirred at room temperature for 3 hours. To the mixture, saturatedaqueous sodium bicarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract solution was washed with waterand saturated brine, followed by drying over anhydrous magnesium sulfateand concentration under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (3.35 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.05 (3H, t, J=7.1 Hz), 2.35 (2H, br s),2.55 (3H, s), 2.90 (2H, br t, J=6.4 Hz), 3.02-3.48 (4H, m), 3.79 (2H, brt, J=6.6 Hz), 3.85-4.09 (4H, m), 4.18-4.50 (2H, m), 4.67-5.06 (3H, m),6.08 (1H, s), 6.59-6.87 (4H, m), 7.20 (1H, d, J=7.7 Hz), 7.38 (2H, br d,J=8.1 Hz), 7.66 (1H, d, J=8.7 Hz). MS m/z 539.3 [M+H]⁺.

H)[32-Methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10)0.^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

To a solution of ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(19 mg) in tetrahydrofuran (0.5 ml) and ethanol (0.5 ml), 2N aqueoussodium hydroxide solution (0.5 mL) was added, and the reaction mixturewas stirred at room temperature for 5 hours. The reaction solution wasneutralized with 2N hydrochloric acid, and then concentrated. Theresidue was purified by preparative HPLC (YMC-Actus Triart C18, mobilephase: 10 mM aqueous ammonium bicarbonate solution/acetonitrile) to givethe title compound (11 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.34-2.60 (2H, m), 2.68 (3H, s), 2.88-3.08(3H, m), 3.12-3.27 (1H, m), 3.30-3.53 (2H, m), 3.69-3.88 (1H, m),3.97-4.15 (3H, m), 4.25 (1H, d, J=13.2 Hz), 4.52 (1H, d, J=12.7 Hz),4.61-4.83 (2H, m), 4.85-4.98 (1H, m), 6.04 (1H, s), 6.70-6.80 (2H, m),6.88 (2H, d, J=8.2 Hz), 7.10-7.25 (2H, m), 7.35 (2H, br t, J=9.2 Hz).

Example 17[18,32-Dimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 18[18-Ethyl-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

A) 3-Ethyl-4-hydroxybenzaldehyde

To a mixture of 3-bromo-4-hydroxybenzaldehyde (10.0 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (3.64 g),cesium carbonate (48.6 g) and tetrahydrofuran (150 ml), 1M solution oftriethylboran in hexane (100 ml) was added. The reaction mixture wasdeaerated by repeatedly reducing the pressure and purging nitrogen, andthen stirred at 70° C. overnight. The reaction mixture was concentratedunder reduced pressure, and water and ethyl acetate were then added tothe residue. After removing the insoluble material by filtration andwashing the residue with ethyl acetate, the filtrate was extracted withethyl acetate. The extract solution was washed with saturated brine,followed by drying over anhydrous magnesium sulfate and concentrationunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (3.71g).

MS m/z 151.1 [M+H]⁺.

B) 2-Ethyl-4-formylphenyl trifluoromethanesulfonate

To a mixture of 3-ethyl-4-hydroxybenzaldehyde (2.10 g),N,N-diisopropltethylamine (4.89 ml), 4-dimethylaminopyridine (0.171 g)and tetrahydrofuran (25 ml), N-phenylbis(trifluoromethanesulfonimide)(5.00 g) was added, and the reaction mixture was stirred at roomtemperature overnight. Water and ethyl acetate were added to thereaction mixture, and the mixture was then extracted with ethyl acetate.The extract solution was washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (3.22 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, t, J=7.6 Hz), 2.78 (2H, q, J=7.6Hz), 7.64 (1H, d, J=8.5 Hz), 7.95 (1H, br d, J=8.6 Hz), 8.07 (1H, s),10.05 (1H, s).

C) Ethyl 2-ethyl-4-formylbenzoate

A mixture of 2-ethyl-4-formylphenyl trifluoromethanesulfonate (3.22 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.835 g),triethylamine (1.59 ml), ethanol (30 ml) and DMF (30 ml) was stirredovernight under heating reflux and under carbon monoxide atmosphere.Then, water and ethyl acetate were added to the reaction mixture. Afterremoving the insoluble material by filtration and washing the residuewith ethyl acetate, the filtrate was extracted with ethyl acetate. Theextract solution was washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.577 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.20 (3H, t, J=7.4 Hz), 1.33 (3H, t, J=7.1Hz), 2.94 (2H, q, J=7.4 Hz), 4.34 (2H, q, J=7.0 Hz), 7.80-7.86 (1H, m),7.87-7.93 (2H, m), 10.06 (1H, s).

D) tert-Butyl 2-ethyl-4-formylbenzoate

To a mixture of ethyl 2-ethyl-4-formylbenzoate (577 mg), ethanol (10.0ml) and tetrahydrofuran (10.0 ml), 2M aqueous sodium hydroxide solution(5.00 ml) was added at room temperature, and the reaction mixture wasstirred at 50° C. overnight. Under reduced pressure, organic solventswere removed, and the residue was then neutralized with 1M hydrochloricacid. The precipitate thus produced was collected by filtration, andwashed with water to obtain a solid. To a mixture of the solid thusobtained and toluene (10 ml), N,N-dimethylformamide di-tert-butylacetal(2.22 ml) was added at 100° C., and the reaction mixture was thenstirred at 100° C. for 1 hour. Additionally, N,N-dimethylformamidedi-tert-butylacetal (2.22 ml) was added, the reaction mixture wasstirred at 100° C. for 2 hours, and then, N,N-dimethylformamidedi-tert-butylacetal (2.22 ml) was further added at 100° C. The reactionmixture was stirred at 100° C. for 30 minutes, and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (420mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.13-1.24 (3H, m), 1.56 (13H, d, J=2.0 Hz),2.83-2.97 (2H, m), 7.69-7.88 (3H, m), 10.05 (1H, s).

E) tert-Butyl 2-ethyl-4-(hydroxymethyl)benzoate

To a mixture of tert-butyl 2-ethyl-4-formylbenzoate (420 mg) andmethanol (10 ml), sodium borohydride (102 mg) was added, and thereaction mixture was stirred at room temperature for 1 hour.Additionally, sodium borohydride (33.9 mg) was added, and the reactionmixture was stirred at room temperature for 1 hour and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (191mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.10-1.20 (3H, m), 1.54 (9H, s), 2.86 (2H,q, J=7.4 Hz), 4.51 (2H, d, J=5.6 Hz), 5.28 (1H, t, J=5.7 Hz), 7.17-7.26(2H, m), 7.63 (1H, d, J=7.9 Hz).

F) tert-Butyl 4-(bromomethyl)-2-ethylbenzoate

To a mixture of tert-butyl 2-ethyl-4-(hydroxymethyl)benzoate (191 mg),triphenylphosphine (318 mg) and tetrahydrofuran (5 ml), carbontetrabromide (402 mg) was added, and the reaction mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract solution waswashed with saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane)twice to give the title compound (178 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (3H, t, J=7.4 Hz), 1.54 (9H, s), 2.84(2H, q, J=7.3 Hz), 4.70 (2H, s), 7.31-7.41 (2H, m), 7.64 (1H, d, J=7.7Hz).

G)[18-Ethyl-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out using tert-butyl4-(bromomethyl)-2-ethylbenzoate in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 19[18-Cyclopropyl-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out using 3-cyclopropyl-4-hydroxybenzaldehyde inaccordance with the methods shown in Example 18 or methods equivalentthereto.

Example 20[32-Methyl-20-oxo-18-(trifluoromethoxy)-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 21[18-Fluoro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 22[18-Methoxy-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 23[32-Methyl-20-oxo-18-(trifluoromethyl)-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 24[18-Chloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 25[32-Methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid <Synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

A) Ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate (chiral, Retention Time Long)

Racemate of ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(3.2 g) was fractionated by preparative supercritical CO₂ chromatographysystem (column: Cellulose-C (5 μm) 250×30 mm I.D., mobile phase: carbondioxide/methanol=70/30). The fraction thus obtained was concentratedunder reduced pressure to give ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate (1.5 g) (chiral, retentiontime long).

Analysis conditions retention time: 5.706 minutes (column: Alcyon SFCCSP Cellulose-C (5 μm), 250×4.6 mm I.D., mobile phase: carbondioxide/methanol=70/30, flow rate: 3.0 mL/min, temperature: 35° C.,detection: UV 210 nm, sample concentration: 1 mg/mL, injection volume:0.005 mL).

B) Ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, Retention Time Short)

Racemate of ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(3.2 g) was fractionated by preparative supercritical CO₂ chromatographysystem (column: Cellulose-C (5 μm) 250×30 mm I.D., mobile phase: carbondioxide/methanol=70/30). The fraction thus obtained was concentratedunder reduced pressure to give ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(1.5 g) (chiral, retention time short).

Analysis conditionsretention time: 4.465 minutes (column: Alcyon SFC CSPCellulose-C (5 μm), 250×4.6 mm I.D., mobile phase: carbondioxide/methanol=70/30, flow rate: 3.0 mL/min, temperature: 35° C.,detection: UV 210 nm, sample concentration: 1 mg/mL, injection volume:0.005 mL).

C)[32-Methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid <Chiral, Synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

To a solution of ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, retention time short) (1.5 g) in tetrahydrofuran (15 ml) andethanol (7.5 ml), 1N aqueous sodium hydroxide solution (14 mL) wasadded, and the reaction mixture was stirred at room temperature for 6hours. Under reduced pressure, organic solvents were removed.Subsequently, the reaction solution was diluted with water, and thenmade acidic with 1N hydrochloric acid at 0° C. The precipitate wasseparated by filtration, washed with water, and then recrystallized froma mixture of ethanol (50 ml) and water (45 ml) to give the titlecompound (1.37 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.35 (2H, br s), 2.54 (3H, s), 2.90 (2H, brt, J=6.5 Hz), 2.96-3.20 (2H, m), 3.35-3.47 (2H, m), 3.72-3.83 (2H, m),3.84-4.09 (2H, m), 4.19-4.32 (1H, m), 4.36-4.46 (1H, m), 4.66-4.90 (3H,m), 6.07 (1H, s), 6.66-6.85 (4H, m), 7.20 (1H, d, J=8.1 Hz), 7.33-7.45(2H, m), 7.65 (1H, d, J=8.5 Hz), 11.86-12.62 (1H, m).

Analysis conditionsretention time: 22.3 minutes, column: DAICELCHIRALPAK IB N-5 (5 μm, 250×4.6 mm I.D.), mobile phase: AB=82.5/17.5,A=hexane (0.1% trifluoroacetic acid), B=ethanol (0.1% trifluoroaceticacid), flow rate: 2.0 mL/min, detection: UV 220 nm and 254 nm,measurement temperature: room temperature, sample concentration: 0.5mg/mL, injection volume: 0.01 mL.

Example 26[32-Methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid <Chiral, Synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Long)>

To a solution of ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, retention time long) (1.5 g) in tetrahydrofuran (15 ml) andethanol (7.5 ml), 1M aqueous sodium hydroxide solution (13.9 mL) wasadded, and the reaction mixture was stirred at room temperatureovernight. Under reduced pressure, organic solvents were removed.Subsequently, the reaction solution was diluted with water, and thenmade acidic with 1N hydrochloric acid at 0° C. The precipitate wasseparated by filtration, and recrystallized using ethanol (38 ml) andwater (38 ml) to give the title compound (1.38 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.35-2.36 (2H, m), 2.54 (3H, s), 2.87-3.18(4H, m), 3.25-3.51 (2H, m), 3.79 (2H, br t, J=6.3 Hz), 3.85-4.09 (2H,m), 4.20-4.52 (2H, m), 4.71-4.91 (3H, m), 6.07 (1H, s), 6.66-6.82 (4H,m), 7.20 (1H, d, J=7.8 Hz), 7.34-7.44 (2H, m), 7.65 (1H, d, J=8.3 Hz),12.27 (1H, s).

Analysis conditionsretention time: 32.4 minutes, column: DAICELCHIRALPAK IB N-5 (5 μm, 250×4.6 mm I.D.), mobile phase: A/B=82.5/17.5,A=hexane (0.1% trifluoroacetic acid), B=ethanol (0.1% trifluoroaceticacid), flow rate: 2.0 mL/min, detection: UV 220 nm and 254 nm,measurement temperature: room temperature, sample concentration: 0.5mg/mL, injection volume: 0.01 mL.

Example 27 Ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate

Synthesis was carried out in accordance with the methods shown inExample 16 or methods equivalent thereto.

Example 282-Methyl-2[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoicAcid

A) tert-Butyl4-{[3-(5-cyano-4-methyl-1H-benzotriazol-1-yl)propoxy]methyl}benzoate

To a solution of tert-butyl4-{[3-(5-bromo-4-methyl-1H-benzotriazol-1-yl)propoxy]methyl}benzoate(1.4 g) in N, N-dimethylformamide (20 ml),tetrakis(triphenylphosphine)palladium (0) (351 mg) and zinc cyanide(1.07 g) were added, and the reaction mixture was stirred at 120° C.overnight. To the reaction solution, saturated aqueous ammonium chloridesolution was added, and the reaction mixture was extracted with ethylacetate. The extract solution was separated and washed with water andsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (1.16 g).

¹H NMR (300 MHz, CDCl₃) δ 1.61 (9H, s), 2.32 (2H, quin, J=6.2 Hz), 3.01(3H, s), 3.43 (2H, t, J=5.6 Hz), 4.48 (2H, s), 4.79 (2H, t, J=6.7 Hz),7.32 (2H, d, J=8.3 Hz), 7.40 (1H, d, J=8.6 Hz), 7.58 (1H, d, J=8.6 Hz),7.89-8.05 (2H, m).

B) tert-Butyl4-{[3-(5-formyl-4-methyl-1H-benzotriazol-1-yl)propoxy]methyl}benzoate

To a mixture of tert-butyl4-{[3-(5-cyano-4-methyl-1H-benzotriazol-1-yl)propoxy]methyl}benzoate (1g), acetic acid (7 ml), pyridine (7 ml) and water (7 ml), aqueoussuspension of Raney nickel (1.5 ml) was added, and the reaction mixturewas stirred overnight under hydrogen atmosphere. After filtering offRaney nickel, water was added to the reaction solution, and the solutionwas extracted with ethyl acetate. The extract solution was washed withsaturated aqueous sodium bicarbonate solution and brine, followed bydrying over anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (450 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.60 (9H, s), 2.23-2.41 (2H, m), 3.17 (3H, s),3.44 (2H, t, J=5.6 Hz), 4.48 (2H, s), 4.79 (2H, t, J=6.7 Hz), 7.30-7.43(3H, m), 7.96 (3H, dd, J=8.5, 2.0 Hz), 10.52 (1H, s). MS m/z 410.3[M+H]⁺.

C) tert-Butyl7-{[1-(3-{[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4-methyl-1H-benzotriazol-5-yl](hydroxy)methyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a mixture of tert-butyl4-{[3-(5-formyl-4-methyl-1H-benzotriazol-1-yl)propoxy]methyl}benzoate(330 mg), potassium phosphate (513 mg), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(2 g), CPME (20 ml) and water (4 ml), chloro(1,5-cyclooctadiene)rhodium(I) dimer (80 mg) was added at room temperature. The mixture was stirredat 110° C. for 1 hour under argon atmosphere. To the mixture thusobtained, saturated aqueous ammonium chloride solution was added, andthe mixture was extracted with ethyl acetate. The extract solution waswashed with saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andsilica gel column chromatography (NH, ethyl acetate/hexane) to give thetitle compound (260 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 1.57-1.63 (9H, m), 2.20-2.41(2H, m), 2.60 (1H, br d, J=2.0 Hz), 2.70-2.89 (5H, m), 3.29-3.51 (2H,m), 3.62 (2H, br t, J=5.7 Hz), 4.40-4.57 (4H, m), 4.73 (2H, t, J=6.6Hz), 6.23 (1H, d, J=3.2 Hz), 7.04-7.18 (3H, m), 7.27-7.37 (3H, m), 7.64(1H, d, J=8.7 Hz), 7.89 (2H, d, J=8.3 Hz).

D)4-[(3-{5-[3-Methoxy-2,2-dimethyl-3-oxo-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)propyl]-4-methyl-1H-benzotriazol-1-yl}propoxy)methyl]benzoicAcid

To a solution of tert-butyl7-{[1-(3-{[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4-methyl-1H-benzotriazol-5-yl](hydroxy)methyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate(50 mg) in acetonitrile (0.5 ml), 2,2,2-trichloroacetonitrile (22.5 mg)was added at room temperature. After stirring the reaction mixture for 5minutes, 1,8-diazabicyclo[5.4.0]-7-undecene (2.4 mg) was added thereto.The reaction solution was stirred at room temperature for 30 minutes,and (1-methoxy-2-methyl-prop-1-enoxy)-trimethyl-silane (79 ul) and1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (5 mg)were added thereto. After stirring the reaction solution at roomtemperature for 2 hours, saturated aqueous sodium bicarbonate solutionwas added thereto, and the mixture was extracted with ethyl acetate. Theextract solution was washed with water and saturated brine, followed bydrying over anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane, ethyl acetate/methanol) to give a mixture. Tothe mixture, 4M HCl/CPME solution (2 ml) was added to give the titlecompound. The residue thus obtained was used for next reaction withoutpurification.

E) Methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoate

To a solution of the residue obtained in the previous step inN,N-dimethylformamide (1.5 ml), N,N-diisopropylethylamine (0.062 mL) wasadded at 0° C. The solution thus obtained was added dropwise to asolution of HATU (40 mg) in N,N-dimethylformamide (2 ml) at roomtemperature over 1 hour. The mixture was stirred at room temperature for3 hours. To the mixture, saturated aqueous sodium bicarbonate solutionwas added, and the mixture was extracted with ethyl acetate. The extractsolution was washed with water and saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound. The residue thusobtained was used for next reaction without further purification.

F)2-Methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoicAcid

To a solution of the residue obtained in the previous step indimethylsulfoxide (0.25 ml), potassium trimethylsilanolate (16.2 mg) wasadded at room temperature. After stirring the mixture at 50° C. for 8hours, further potassium trimethylsilanolate (8 mg) was added at roomtemperature. After stirring the mixture at 50° C. overnight, water wasadded to the mixture, and the mixture was extracted with ethyl acetate.The extract solution was washed with water and saturated brine, followedby drying over anhydrous magnesium sulfate and concentration underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol). To the residue thus obtained,water was added, and the precipitate was separated by filtration to givethe title compound (7 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.18 (3H, s), 1.32 (3H, s), 2.31-2.42 (3H,m), 2.85-2.95 (2H, m), 3.36-3.44 (3H, m), 3.57-3.76 (1H, m), 3.83-4.15(3H, m),4.23-4.45 (2H, m), 4.73-4.82 (3H, m), 6.13 (1H, s), 6.63-6.80(4H, m), 7.17 (1H, d, J=8.0 Hz), 7.33-7.42 (1H, m), 7.44-7.53 (1H, m),7.61 (1H, d, J=9.0Hz), 12.36 (1H, s).

Example 29[32-Methyl-20-oxo-13-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

A) 2-{2-[2-(4-Bromophenyl)ethoxy]ethoxyl}oxane

To a solution of 2-(4-bromophenyl)ethanol (1 g) in N,N-dimethylformamide(20 ml), sodium hydride (50%, 597 mg) was added at 0° C. After stirringthe reaction mixture at 0° C. for 1 hour,2-(2-bromoethoxy)tetrahydropyran (2.08 g) was added at 0° C. The mixturewas stirred at room temperature for 2 hours. To the mixture, saturatedaqueous ammonium chloride solution was added, and the mixture wasextracted with ethyl acetate. The organic layer was separated and washedwith saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (907 mg). MS m/z 353.2 [M+Na]⁺.

B) 4-(2-{2-[(Oxan-2-yl)oxy]ethoxyl}ethyl)benzoic Acid

To a solution of 2-{2-[2-(4-bromophenyl)ethoxy]ethoxy}oxane (2.81 g) intetrahydrofuran (30 ml), n-butyllithium (1.6M solution in hexane, 8.01ml) was added at −78° C., and the reaction mixture was stirred at thesame temperature for 1 hour. Carbon dioxide generated from dry ice waspassed through the reaction solution at −78° C., and the solution wasstirred at the same temperature for 1 hour, and stirred at roomtemperature overnight. To the mixture, 1M hydrochloric acid was addedfor neutralization, and the mixture was then extracted with ethylacetate. The organic layer was separated and washed with saturatedbrine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.76 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.30-1.78 (6H, m), 2.88 (2H, br t, J=6.6Hz), 3.24-3.60 (4H, m), 3.61-3.76 (4H, m), 4.53 (1H, br s), 7.37 (2H, d,J=7.9 Hz), 7.85 (2H, d, J=8.0 Hz), 12.59-12.88 (1H, m).

C) tert-Butyl 4-[2-(2-hydroxyethoxy)ethyl]benzoate

To a solution of 4-(2-{2-[(oxan-2-yl)oxy]ethoxy}ethyl)benzoic acid (1.76g) in toluene (20 ml), 1,1-di-tert-butoxy-N,N-dimethyl-methanamine (6.08g) was added at 100° C., and the reaction mixture was stirred at thesame temperature for 1 hour. Further,1,1-di-tert-butoxy-N,N-dimethyl-methanamine (6.08 g) was added at 100°C., and the reaction mixture was stirred at the same temperature for 2hours. The reaction solution was concentrated, and the residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (1.47 g). The residue thus obtained was used fornext reaction without further purification. To a mixture of the residuethus obtained (1.47 g) in ethanol (15 ml), pyridinium p-toluenesulfonate(105 mg) was added at 50° C., and the reaction mixture was stirred atthe same temperature for 2 hours. To the reaction solution,triethylamine was added at room temperature, and the solution wasconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.1g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.54 (9H, s), 2.88 (2H, t, J=6.8 Hz),3.37-3.52 (4H, m), 3.62 (2H, t, J=6.6 Hz), 4.57 (1H, t, J=5.1 Hz), 7.37(2H, br d, J=7.9 Hz), 7.81 (2H, d, J=8.0 Hz).

D) tert-Butyl4-(2-{2-[(4-methylbenzene-1-sulfonyl)oxy]ethoxy}ethyl)benzoate

To a mixture of tert-butyl 4-[2-(2-hydroxyethoxy)ethyl]benzoate (1.14g), p-toluenesulfonyl chloride (1.63 g), 4-dimethylaminopyridine (52.3mg), triethylamine (2.39 ml) and tetrahydrofuran (10 ml), the reactionmixture was stirred at room temperature for 5 hours. To the reactionsolution, triethylamine (1.2 ml) and p-toluenesulfonyl chloride (815 mg)were added, and the reaction solution was stirred at room temperaturefor 3 days. Water was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was separated andwashed with saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (1.62 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.54 (9H, s), 2.42 (3H, s), 2.80 (2H, br t,J=6.5 Hz), 3.50-3.59 (4H, m), 4.05-4.13 (2H, m), 7.30 (2H, d, J=8.0 Hz),7.47 (2H, br d, J=8.1 Hz), 7.72-7.83 (4H, m). MS m/z 443.2 [M+Na]⁺.

E) tert-Butyl4-{2-[2-(4-bromo-3-methyl-2-nitroanilino)ethoxy]ethyl}benzoate

A solution of tert-butyl4-(2-{2-[(4-methylbenzene-1-sulfonyl)oxy]ethoxy}ethyl)benzoate (1.32 g),4-bromo-3-methyl-2-nitro-aniline (869 mg) and cesium carbonate (2.04 g)in N,N-dimethylformamide (15 ml) was stirred at 80° C. overnight. Waterwas added to the mixture, and the mixture was extracted with ethylacetate. The organic layer was separated and washed with saturatedbrine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (761 mg). MS m/z 501.2 [M+Na]⁺.

F) tert-Butyl4-{2-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethoxy]ethyl}benzoate

A mixture of tert-butyl4-{2-[2-(4-bromo-3-methyl-2-nitroanilino)ethoxy]ethyl}benzoate (761 mg),ammonium chloride (849 mg), iron (443 mg), ethanol (10 ml) and water (2ml) was stirred at 80° C. for 3 hours. To the mixture thus obtained,water was added, and the mixture was extracted with ethyl acetate. Theextract solution was washed with saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (299 mg). The residuethus obtained was used for next reaction without further purification.

To a mixture of the residue thus obtained in acetic acid (3 ml) andwater (0.5 ml), a solution of sodium nitrite (91.8 mg) in water (1 ml)was added at 0° C. After stirring the mixture at 0° C. for 30 minutes,water was added to the mixture, and the mixture was extracted with ethylacetate. The extract solution was washed with water, saturated aqueoussodium bicarbonate solution, and saturated brine, followed by dryingover anhydrous magnesium sulfate and concentration under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) and silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (223 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.60 (9H, s), 2.74-2.82 (2H, m), 2.84 (3H, s),3.59 (2H, t, J=6.5 Hz), 3.89 (2H, t, J=5.0 Hz), 4.74 (2H, t, J=5.0 Hz),7.07 (2H, br d, J=7.9 Hz), 7.21 (1H, br d, J=8.5 Hz), 7.51 (1H, d, J=8.6Hz), 7.82 (2H, br d, J=7.8 Hz).; MS m/z 460.1 [M+H]⁺;

G) tert-Butyl4-[2-(2-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}ethoxy)ethyl]benzoate

To a solution of tert-butyl4-{2-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethoxy]ethyl}benzoate(148 mg), ethyl acrylate (0.211 ml) and N,N-diisopropylethylamine (0.225ml) in N,N-dimethylformamide (2.5 ml), tri(o-tolyl)phosphine (29.4 mg)and palladium acetate (11 mg) were added, and the reaction mixture wasstirred at 120° C. for 4 hours under microwave irradiation. To themixture thus obtained, water was added, and the mixture was extractedwith ethyl acetate. The extract solution was washed with saturatedbrine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (163 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7.1 Hz), 1.58 (9H, s),2.74-2.83 (2H, m), 2.92 (3H, s), 3.60 (2H, t, J=6.5 Hz), 3.90 (2H, br t,J=4.9 Hz), 4.30 (2H, q, J=7.2 Hz), 4.75 (2H, t, J=4.8 Hz), 6.42 (1H, d,J=16.0 Hz), 7.07 (2H, br d, J=8.0 Hz), 7.34 (1H, d, J=8.8 Hz), 7.64 (1H,d, J=8.7 Hz), 7.81 (2H, br d, J=8.0 Hz), 8.15 (1H, d, J=16.0 Hz).

MS m/z 480.3 [M+H]⁺.

H) tert-Butyl7-{1-[1-(2-{2-[4-(tert-butoxycarbonyl)phenyl]ethoxy}ethyl)-4-methyl-1H-benzotriazol-5-yl]-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a mixture of tert-butyl4-[2-(2-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}ethoxy)ethyl]benzoate(163 mg), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(147 mg), sodium dodecyl sulfate (49.1 mg), triethylamine (0.14 ml),CPME (2 ml) and water (1 ml), chloro(1,5-cyclooctadiene)rhodium (I)dimer (16.8 mg) was added at room temperature. The mixture was stirredat 100° C. overnight. Water was added to the mixture thus obtained, andthe mixture was extracted with ethyl acetate. The extract solution waswashed with saturated brine, followed by drying over anhydrous magnesiumsulfate and concentration under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to give the title compound (126 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.10 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.59(9H, s), 2.70-2.83 (4H, m), 2.86 (3H, s), 2.98-3.19 (2H, m), 3.59 (4H,br t, J=6.2 Hz), 3.89 (2H, br t, J=5.0 Hz), 4.02 (2H, q, J=7.1 Hz),4.42-4.52 (2H, m), 4.72 (2H, t, J=5.0 Hz), 4.96 (1H, br t, J=7.8 Hz),6.91-6.97 (1H, m), 7.00-7.06 (2H, m), 7.11 (2H, br d, J=8.0 Hz),7.30-7.36 (2H, m), 7.84 (2H, d, J=8.1 Hz).

MS m/z 713.4 [M+H]⁺.

I) Ethyl[32-methyl-20-oxo-13-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate

To a solution of tert-butyl7-{1-[1-(2-{2-[4-(tert-butoxycarbonyl)phenyl]ethoxy}ethyl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate(139 mg) in CPME (1.5 ml), 4N HCl/CPME solution (1.27 ml) was added atroom temperature. The mixture was stirred at room temperature for 2hours, and then concentrated. The residue thus obtained was used fornext reaction without purification.

A solution of the residue thus obtained and N,N-diisopropylethylamine(0.17 ml) in N,N-dimethylformamide (10 ml) was added dropwise to asolution of HATU (111 mg) in N,N-dimethylformamide (10 ml) at roomtemperature over 30 minutes. The mixture was stirred at room temperaturefor 3.5 hours. Water was added to the mixture, and the mixture wasextracted with ethyl acetate. The extract solution was washed withsaturated brine, followed by drying over anhydrous magnesium sulfate andconcentration under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane, methanol/ethyl acetate)and silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (80 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.13 (3H, t, J=7.1 Hz), 2.68-2.91 (5H, m),2.94-3.11 (3H, m), 3.17-3.29 (1H, m), 3.52-3.63 (1H, m), 3.66-3.76 (1H,m), 3.77-3.90 (1H, m), 3.91-4.19 (7H, m), 4.63-4.78 (1H, m), 4.91-5.05(2H, m), 6.29 (1H, s), 6.76-6.85 (4H, m), 7.19 (1H, d, J=8.0 Hz),7.30-7.40 (2H, m), 7.49 (1H, d, J=8.7 Hz).

MS m/z 539.3 [M+H]⁺.

J)[32-Methyl-20-oxo-13-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

To a solution of ethyl[32-methyl-20-oxo-13-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(105 mg) in tetrahydrofuran (1.5 ml) and ethanol (1.5 ml), 4M aqueouslithium hydroxide solution (0.5 ml) was added, and the reaction mixturewas stirred at room temperature for 2 hours. To the reaction solution,4M aqueous lithium hydroxide solution (0.5 ml) was further added, andthe reaction solution was stirred at room temperature for 1 hour. Thereaction solution was concentrated, water (3 ml) was added to theresidue, and the solution was neutralized at 0° C. with 2N hydrochloricacid. The precipitate was filtered to give the title compound (72.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.58 (3H, s), 2.68-2.79 (2H, m), 2.87-2.96(2H, m), 2.96-3.08 (1H, m), 3.08-3.20 (1H, m), 3.50-3.68 (2H, m),3.69-3.81 (2H, m), 3.94-4.10 (4H, m), 4.74-4.84 (1H, m), 4.87-4.96 (2H,m), 6.30 (1H, s), 6.59-6.66 (2H, m), 6.69-6.77 (2H, m), 7.21 (1H, d,J=7.5 Hz), 7.38-7.50 (2H, in), 7.70 (1H, d, J=8.5 Hz), 12.19-12.34 (1H,m).

Example 30

[32-Methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 9 or methods equivalent thereto.

Example 31[18-Fluoro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 9 or methods equivalent thereto.

Example 32[18,30-Difluoro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticAcid

Synthesis was carried out in accordance with the methods shown inExample 9 or methods equivalent thereto.

Example 33[6,6,33-Trimethyl-2-oxo-7,10-dioxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

A) Methyl 4-(benzyloxy)-3-hydroxy-2-(2-methylprop-2-en-1-yl)benzoate

The title compound was obtained using methyl3-hydroxy-4-phenylmethoxybenzoate in accordance with the methods shownin Example 8A) to Example 8B) or methods equivalent thereto.

MS m/z 313.2 [M+H]⁺.

B) Methyl 7-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-carboxylate

A mixture of methyl4-(benzyloxy)-3-hydroxy-2-(2-methylprop-2-en-1-yl)benzoate (390 mg),formic acid (5 ml) and water (0.5 ml) was stirred at 100° C. overnight.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (125 mg).

MS m/z 223.2 [M+H]⁺.

C)2,2-Dimethyl-7-[(prop-2-en-1-yl)oxy]-2,3-dihydro-1-benzofuran-4-carboxylicAcid

The title compound was obtained using methyl7-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-carboxylate inaccordance with the methods shown in Example 30 A) to Example 30 B) ormethods equivalent thereto.

MS m/z 249.1 [M+H]⁺.

D)[6,6,33-Trimethyl-2-oxo-7,10-dioxa-1,15,16,17-tetraazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta-3,8,16,18(33),19,21,24,26,31,34-decaen-23-yl]aceticAcid

The title compound was obtained using2,2-dimethyl-7-[(prop-2-en-1-yl)oxy]-2,3-dihydro-1-benzofuran-4-carboxylicacid in accordance with the methods shown in Example 9 L) to Example 9N) or methods equivalent thereto.

Example 34 (5-Methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate<Chiral, Synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

To a solution of[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid <52.6 mg, chiral, synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(retention time short)> in N,N-dimethylformamide (0.5 ml), potassiumcarbonate (28.5 mg) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one(0.011 ml) were added, and the reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate, andwashed with water and saturated brine. The mixture was then dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (25 mg).

Example 35 (5-Methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate<Synthesis from chiral ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Long)>

Synthesis was carried out in accordance with the methods shown inExample 34 or methods equivalent thereto.

Example 36 Ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, Retention Time Short)

Synthesis was carried out using iodoethane in accordance with themethods shown in Example 34 or methods equivalent thereto.

Example 37 Ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(chiral, Retention Time Short)

Synthesis was carried out using iodoethane in accordance with themethods shown in Example 34 or methods equivalent thereto.

Example 382-[32-Methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-N-(6-methylpyridin-3-yl)acetamide<Chiral, Synthesis from chiral ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

To a mixture of[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid <25 mg, chiral, synthesis from chiral ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(retention time short)> and N,N-dimethylformamide (0.25 ml),triethylamine (0.0138 ml), HOBt (8 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.3 mg)and 6-methylpyridine-3-amine (6 mg) were added, and the reaction mixturewas stirred at room temperature overnight. To the mixture, saturatedaqueous sodium bicarbonate solution was added, and the precipitate wasseparated by filtration. The solid was washed with ethyl acetate to givethe title compound (20 mg).

Example 392-[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-N-(pyridin-3-yl)acetamide<Chiral, Synthesis from chiral ethyl[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

Synthesis was carried out in accordance with the methods shown inExample 38 or methods equivalent thereto.

Example 40 1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate<Synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

To a solution of[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid <53.3 mg, chiral, synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(retention time short)> in N,N-dimethylformamide (0.5 ml), cesiumcarbonate (51 mg) and 1-chloroethyl cyclohexyl carbonate (34.5 mg) wereadded, and the reaction mixture was stirred at room temperatureovernight. The mixture was diluted with ethyl acetate, and washed withwater and saturated brine. The mixture was then dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane).After suspending the residue thus obtained with water, the suspensionwas concentrated to give the title compound (49 mg).

Example 41 Sodium[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate<Synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(Retention Time Short)>

To a mixture of[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid <synthesis from chiral ethyl[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetate(retention time short)> (42.7 mg) in methanol (0.5 ml), 2N sodiumhydroxide (0.0418 ml) was added at room temperature. The reactionsolution was concentrated to give the title compound (40 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.25-2.41 (2H, m), 2.53-2.68 (2H, m), 2.88(2H, t, J=6.7 Hz), 3.35-3.47 (2H, m), 3.77 (2H, t, J=6.7 Hz), 3.82-4.08(2H, m), 4.20-4.30 (1H, m), 4.34-4.46 (1H, m), 4.67-4.91 (3H, m), 5.96(1H, s), 6.67-6.74 (2H, m), 6.74-6.87 (2H, m), 7.14 (1H, d, J=7.9 Hz),7.35 (1H, d, J=8.6 Hz), 7.43 (1H, d, J=7.9 Hz), 7.57 (1H, d, J=8.6 Hz).

Example 422-[32-Methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-N-(6-methylpyridin-3-yl)acetamide

Synthesis was carried out in accordance with the methods shown inExample 38 or methods equivalent thereto.

Compounds of Examples 43 to 54 can be produced in accordance with themethods shown in Example 28 described above or methods equivalentthereto.

Example 432-[18,30-Dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

Example 442-Methyl-2-[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoicAcid

Example 452-Methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoicAcid

Example 462-[18,30-Dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

Example 472-Methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoicAcid

Example 482-[18,30-Dichloro-25,32-dimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

Example 492-Methyl-2-[18,25,30-trichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]propanoicAcid

Example 502-[18,30-Dichloro-32-methyl-20-oxo-25-(trifluoromethyl)-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

Example 512-[8-(Cyclopropylmethyl)-34-methyl-2,7-dioxo-5-oxa-1,8,16,17,18-pentaazaheptacyclo[23.5.3.2^(3,10).1^(19,23).0^(4,9).0^(16,20).0^(28,32)]hexatriaconta-3,9,17,19(34),20,22,25,27,32,35-decaen-24-yl]-2-methylpropanoicAcid

Example 522-[18,30-Dichloro-32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

Example 532-[18,30-Dichloro-5-methoxy-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

Example 542-[18,30-Dichloro-5-methoxy-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

Example 552-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]propanoicAcid <Chiral, synthesis from chiral methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8, 16,18,24(28),25, 30-decaen-2-yl]propanoate (Retention TimeShort)>

A) 1-bromo-4-fluoro-2-methyl-3-nitro-benzene

To a solution of 1-fluoro-3-methyl-2-nitro-benzene (10 g) in TFA (23 mL)and H₂SO₄ (10 mL) was added NBS (14 g) at 0° C. The mixture was stirredat room temperature overnight. The mixture was poured into ice. Theprecipitate was filtrated and washed with water to get title compound(14 g) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.34 (3H, s), 7.46 (1H, t, J=9.3 Hz),7.93-7.97 (1H, m)

B) 3-[(4-Bromo-3-methyl-2-nitrophenyl)amino]propan-1-ol

To a solution of 1-bromo-4-fluoro-2-methyl-3-nitro-benzene (14 g) in DMF(150 mL) was added K₂CO₃ (16.655 g) and 3-amino propanol (6 mL) at roomtemperature. The mixture was stirred at 80° C. overnight. Aftercompletion of reaction, ice-cold water was added to reaction mass at 0°C. The precipitate was filtrated and washed with water. Residue wasevaporated and washed with n-pentane to afford title compound (14 g) asorange solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.68 (2H, q, J=5.9 Hz), 2.24 (3H, s), 3.17(2H, q, J=6.0 Hz), 3.44 (2H, q, J=5.1 Hz), 4.58-4.60 (1H, m), 6.22 (1H,brs), 6.73 (1H, d, J=9.1 Hz), 7.54 (1H, d, J=9.0 Hz). MS m/z 289.2[M+H]⁺.

C) 3-[(2-Amino-4-bromo-3-methylphenyl)amino]propan-1-ol

To a stirred solution of3-[(4-bromo-3-methyl-2-nitrophenyl)amino]propan-1-ol (14.6 g) in ethanol(150 mL) and water (80 mL) were added iron (14.1 g) and NH₄Cl (27 g) at25° C. and reaction mixture was refluxed for 4 h. The reaction mixturewas filtered through celite bed and solvent was evaporated. Residue wasquenched with sat NaHCO₃ aq.. The aqueous layer was extracted with ethylacetate (50 ml×3). The total organic layer was washed with brine, driedover anhydrous Na₂SO₄ and evaporated under reduced pressure to affordtitle compound (11.8 g) as brown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.69-1.76 (2H, quin, J=6.6 Hz), 2.15 (3H,s), 3.18 (2H, q, J=6.5 Hz), 3.49 (2H, q, J=5.7 Hz), 4.45-4.48 (1H, m),4.53-4.64 (3H, m), 6.25 (1H, d, J=8.5 Hz), 6.70 (1H, d, J=8.4 Hz). MSm/z 258.9 [M+H]⁺.

D) 3-(5-Bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl)propan-1-ol

To a solution of 3-[(2-Amino-4-bromo-3-methylphenyl)amino]propan-1-ol(12 g) in 6N HCl (122 mL) was slowly added a solution of NaNO₂ (6.4 g)of water (36 mL) at 0° C. The mixture was stirred at room temperaturefor 2 h. The reaction mixture was neutralized with 4N NaOH at 0° C. Theaqueous layer was extracted with EtOAc, combined organics were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Crude was purified by silica gel column (120 g, 60%EtOAc/Hexane) to afford title compound (11 g) as brown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.03 (2H, quin, J=6.4 Hz), 2.71 (3H, s),3.39 (2H, q, J=5.5 Hz), 4.66 (1H, br t, J=4.7 Hz), 4.74 (2H, t, J=6.7Hz), 7.68 (2H, s).

MS m/z 270.1 [M+H]⁺.

E)4-{[3-(5-Bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl)propoxy]methyl}benzoate

To a stirred solution of3-(5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl)propan-1-ol (11.4 g) inTHF (250 ml), NaH (60% in oil, 10.12 g) was added at 0° C. and stirredat 25° C. for 1 h. To this was added TBAI (31 g) and tert-butyl4-(bromomethyl)benzoate (22.8 g) at 0° C. and stirred at 25° C. for 4 h.The reaction mixture was quenched with ice. The aqueous layer wasextracted with EtOAc, combined organics were washed with brine; driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudethus obtained was purified by silica gel column chromatography (SiO₂;10%EtOAc/Hexanes) to afford title compound (16 g) as light yellowliquid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.17-2.23 (2H, m), 2.67 (3H,s), 3.42 (2H, t, J=5.7 Hz), 4.43 (2H, s), 4.78 (2H, t, J=6.5 Hz), 7.25(2H, d, J=8.1 Hz), 7.65 (2H, m), 7.80 (2H, d, J=8.1 Hz). MS m/z 460.1[M+H]⁺.

F) tert-Butyl4-{[3-(5-cyano-4-methyl-1H-1,2,3-benzotriazol-1-yl)propoxy]methyl}benzoate

In oven dried sealed tube, to a stirred solution of tert-butyl4-{[3-(5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl)propoxy]methyl}benzoate(15 g) in DMA (125 mL) were added Zn(CN)₂ (2.3 g), Zn-dust (0.637 g) at25° C. and the reaction mixture was de gassed with argon atmosphere for10 min. To this was added Pd₂(dba)₃ (1.495 g) followed by dppf (1.8 g)at 25° C. and the reaction mixture was heated at 150° C. for 6 h. Thereaction mixture was cooled to 25° C., filtered through celite andwashed with EtOAc. The filtrate was diluted with water (10 times) andstirred it for 30 min. The aqueous layer was extracted with EtOAc,combined organics were washed with water, brine, dried over anhydrousNa₂SO₄, filtered and filtrate was concentrated under reduced pressure.The crude thus obtained was purified by silica gel column chromatography(SiO₂, 20-25% EtOAc/Hexane) to give title compound (10 g) as colorlesssticky oil.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.22 (2H, t, J=6.1 Hz),2.83-2.85 (3H, m), 3.44 (2H, t, J=5.7 Hz), 4.40 (2H, s), 4.84 (2H, t,J=6.5 Hz), 7.21 (2H, d, J=8.1 Hz), 7.77-7.80 (4H, m). MS m/z 407.0[M+H]⁺.

G) tert-butyl4-{[3-(5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl)propoxy]methyl}benzoate

To a stirred solution of4-{[3-(5-cyano-4-methyl-1H-1,2,3-benzotriazol-1-yl)propoxy]methyl}benzoate(4.7 g) in pyridine (85 mL) were added AcOH (85 mL), water (85 mL)followed by Raney Ni (in water, 47 mL) at 25° C. The reaction mixturewas stirred under positive pressure of hydrogen balloon for 24 h at 25°C. The progress of reaction was judged by LC/MS only. After completionof reaction (as judged by LC/MS), the reaction mixture was filteredthrough celite and washed with EtOAc. Filtrate was diluted with ethylacetate, washed with 0.5M citric acid, saturated aqueous NaHCO₃,combined organics were washed with water, brine, dried over anhydrousNa₂SO₄, filtered and filtrate was concentrated under reduced pressure.The crude thus obtained was purified by silica gel column chromatography(SiO₂, 30-35% EtOAc/Hexane) to give title compound (2.3 g) as brown oil.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.21-2.26 (2H, m), 3.04 (3H,s), 3.43 (2H, t, J=5.8 Hz), 4.43 (2H, s), 4.82 (2H, t, J=6.6 Hz), 7.28(2H, d, J=8.0 Hz), 7.77-7.80 (3H, m), 7.92 (1H, d, J=8.6 Hz), 10.43 (1H,s). MS m/z 410.4 [M+H]⁺.

H) tert-Butyl7-({1-[3-({4-[(tert-butoxy)carbonyl]phenyl}methoxy)propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl}(hydroxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a degassed solution of tert-butyl4-{[3-(5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl)propoxy]methyl}benzoate(2.6 g) in mixture of CPME (60 ml) and water (12 ml) were addedtert-butyl7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(6.8 g), K₃PO₄ (4.04 g) at 25° C. To this was added [RhCl(COD)]₂ (627mg) and the reaction mixture was heated at 50° C. for 2 h. The reactionmixture was cooled to 25° C. and quenched with sat NH₄Cl aq. The aqueouslayer was extracted with EtOAc, combined organics were washed withwater, brine, dried over anhydrous Na₂SO₄, filtered and filtrate wasconcentrated under reduced pressure. The crude thus obtained waspurified by silica gel column chromatography (SiO₂, 25% EtOAc/Hexane) togive title compound (2 g) as light yellow sticky solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.39 (9H, s), 1.53 (9H, s), 2.19-2.16 (2H,m), 2.68-2.72 (5H, m), 3.41 (2H, t, J=5.88 Hz), 3.48-3.51 (2H, m),4.42-4.46 (4H, m), 4.74 (2H, t, J=6.68 Hz), 5.87-5.88 (1H, m), 6.03-6.04(1H, m), 7.04-7.12 (3H, m), 7.34 (2H, d, J=8.04 Hz), 7.58 (2H, s), 7.83(2H, d, J=8.12 Hz). MS m/z 643.1 [M+H]⁺.

I)4-[(3-{5-[3-Methoxy-2,2-dimethyl-3-oxo-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl}propoxy)methyl]benzoicAcid

To a stirred solution of tert-Butyl7-({1-[3-({4-[(tert-butoxy)carbonyl]phenyl}methoxy)propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl}(hydroxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(700 mg) in DCM (30 mL) were added[(1-methoxy-2-methylprop-1-en-1-yl)oxy]trimethylsilane (1.2 mL) andTiCl₄ (1M in DCM, 2.4 mL) at 0° C. and the reaction mixture was stirredat 0° C. for 5 min. After completion of reaction (as jugged by LCMS andTLC), the reaction mixture was quenched with water. Aqueous layer wasbasified with saturated NaHCO₃ solution (pH˜8) and filtered throughcelite bed. After filtration, aqueous layer was extracted with 10%MeOH/DCM (3×50 mL), the combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and evaporated to give a mixture, which wasused to next step without further purification.

To a mixture in dioxane (6 mL) was added 4M HCl/dioxane solution (6 mL)dropwise at 25° C. and the reaction mixture was stirred at thattemperature for 2 h. After completion of reaction (as judged by LC/MS),the volatiles were removed under reduced pressure and crude thusobtained was purified by reverse phase prep-HPLC to give title compound(250 mg) as off white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.24-1.29 (6H, m), 2.18 (2H, t, J=5.8 Hz),2.67-2.71 (5H, m), 3.07-3.08 (2H, m), 3.33-3.42 (2H, m), 3.42 (3H, s),3.95 (214, s), 4.28-4.38 (2H, m), 4.70-4.73 (3H, m), 6.95 (1H, d, J=7.7Hz), 7.01-7.09 (4H, m), 7.47-7.54 (2H, m), 7.61 (2H, d, J=7.9 Hz).

MS m/z 571.2 [M+H]⁺.

J) methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeShort) and methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeLong)

To a solution of HATU (406 mg) in DMF (15 ml) was added a mixture of4-[[3-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2, 3-benzotriazol-1-yl]propoxy]methyl]benzoic acid (500 mg) andN,N-diisopropylethylamine (0.74 mL) in DMF (32 ml) at 25° C. by syringepump for 1 h and the reaction mixture was stirred at that temperaturefor 3 h. After completion of reaction (as judged by LC/MS), reactionmixture was diluted with saturated NaHCO₃ solution. The aqueous layerwas extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and evaporated under reducedpressure. The crude thus obtained was purified by normal phase chiralHPLC (method C) to afford methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8, 16,18,24(28),25,30-decaen-2-yl]propanoate (retention timeshort) (55 mg) and methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (retention timelong) (45 mg) as white solid.

methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeShort)

¹H NMR (400 MHz, DMSO-d₆): δ 1.22-1.34 (6H, m), 2.32-2.36 (2H, m), 2.90(2H, brs), 3.35-3.38 (4H, m), 3.48 (3H, s), 3.50-3.65 (1H, m), 3.86-3.90(1H, m), 4.00-4.03 (2H, m), 4.10-4.14 (1H, m), 4.25-4.29 (1H, m),4.37-4.40 (1H, m), 4.76-4.78 (3H, m), 6.17 (1H, s), 6.66 (2H, d, J=7.8Hz), 6.76 (2H, d, J=8.1 Hz), 7.18 (1H, d, J=8.0 Hz), 7.31 (1H, d, J 6.5Hz), 7.41 (1H, d, J=8.9 Hz), 7.61 (1H, d, J=8.9 Hz). MS m/z 553.0[M+H]⁺.

methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeLong)

¹H NMR (400 MHz, DMSO-d6): δ 1.22-1.34 (6H, m), 2.32-2.36 (1H, m),2.90-2.95 (2H, m), 3.35-3.38 (4H, m), 3.48 (3H, s), 3.62-3.63 (1H, m),3.86-3.90 (1H, m), 4.00-4.03 (2H, m), 4.10-4.14 (1H, m), 4.26-4.29 (1H,m), 4.37-4.40 (1H, m), 4.78 (3H, s), 6.17 (1H, s), 6.66 (2H, d, J=7.5Hz), 6.76 (2H, d, J=7.8 Hz), 7.18 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=8.0Hz), 7.41 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=8.8 Hz).

MS m/z 553.2 [M+H]⁺.

K)2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]propanoicAcid <Chiral, Synthesis from chiral methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8, 16,18,24(28),25,30-decaen-2-yl]propanoate (Retention TimeShort)>

To a stirred solution of chiral methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8, 9, 10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8, 16,18,24(28),25,30-decaen-2-yl]propanoate (retention timeshort) (80 mg) in DMSO (1.5 ml) was added TMSOK (92 mg) at 25° C. andthe reaction mixture was heated at 50° C. for 3 h. After completion ofreaction (as jugged by TLC & LC/MS), the reaction mixture was cooled to25° C. The reaction mixture was diluted with EtOAc and neutralized with1N HCl. The aqueous layer was extracted with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ and evaporatedunder reduced pressure The crude thus obtained was purified by reversephase prep-HPLC (method A) to give title compound (21.15 mg) as whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.22-1.32 (6H, m), 2.36 (2H, brs), 2.90(2H, brs), 3.35-3.38 (4H, m), 3.65-3.67 (1H, m), 3.86-3.96 (3H, m),4.08-4.12 (1H, m), 4.25-4.28 (1H, m), 4.37-4.40 (1H, m), 4.76-4.79 (3H,m), 6.13 (1H, s), 6.67 (2H, d, J=7.4 Hz), 6.76 (2H, d, J=7.7 Hz), 7.18(1H, d, J=7.7 Hz), 7.37 (1H, d, J=7.5 Hz), 7.47 (1H, d, J=8.6 Hz), 7.61(1H, d, J=8.5 Hz), 12.35 (1H, bs). MS m/z 539.4 [M+H]⁺.

Example 562-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]propanoicAcid <Chiral, Synthesis from chiral methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8, 9, 10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8, 16,18,24(28),25,30-decaen-2-yl]propanoate (Retention TimeLong)>

To a stirred solution of chiral methyl2-methyl-2-[32-methyl-20-oxo-14-oxa-8, 9, 10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8, 16,18,24(28),25,30-decaen-2-yl]propanoate (retention timelong) (73 mg) in DMSO (1.5 ml) was added TMSOK (84 mg) at 25° C., andthe reaction mixture was heated at 50° C. for 3 h. After completion ofreaction (as jugged by TLC and LC/MS), the reaction mixture was cooledto 25° C. The reaction mixture was diluted with EtOAc and neutralizedwith 1N HCl. The aqueous layer was extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andevaporated under reduced pressure The crude thus obtained was purifiedby reverse phase prep-HPLC (method A) to give title compound (16.42 mg)as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.18-1.32 (6H, m), 2.36 (2H, brs), 2.90(2H, brs), 3.35-3.38 (4H, m), 3.64 (1H, brs), 3.86-3.99 (3H, m),4.09-4.12 (1H, m), 4.25-4.28 (1H, m), 4.37-4.40 (1H, m), 4.76-4.79 (3H,m), 6.13 (1H, s), 6.67 (21-1, d, J=7.6 Hz), 6.76 (2H, d, J=7.7 Hz), 7.18(1H, d, J=7.6 Hz), 7.37 (1H, d, J=8.0 Hz), 7.47 (1H, d, J=8.6 Hz), 7.61(1H, d, J=8.7 Hz), 12.35 (1H, bs). MS m/z 539.4 [M+H]⁺.

Example 572-[18,30-dichloro-32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]-2-methylpropanoicAcid

The compounds of Examples 57 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 582-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoicAcid <Chiral, Synthesis from chiral methyl2-methyl-2[18,30,32-trimethyl-20-oxo-14-oxa-8, 9, 10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18,24(28),25,30-decaen-2-yl]propanoate (Retention TimeShort)>

A) tert-butyl 4-bromo-2,6-dimethylbenzoate

A solution of 4-bromo-2,6-dimethyl-benzoic acid (1 g) in toluene (10 ml)was heated to 100° C. for 1 h. To this was added N,N-dimethylformamidedi-tert-butyl acetal (6.2 ml) in toluene (5 ml) dropwise at heatingcondition, and the reaction mixture was stirred for another 1 h at thattemperature. After completion of reaction (as jugged by TLC), thevolatiles were evaporated under reduced pressure. The crude thusobtained was purified by silica gel column chromatography (SiO₂, 40 g,12% EtOAc/Hexane) to give title compound (840 mg) as colorless oil.

¹H NMR (400 MHz, DMSO-d₆): δ 1.53 (9H, s), 2.24 (6H, s), 7.32 (2H, s).

B) tert-butyl 4-formyl-2,6-dimethylbenzoate

To a stirred solution of tert-butyl 4-bromo-2,6-dimethylbenzoate (2 g)in THF (20 ml) was added n-BuLi (1.6M in hexane) (4.4 ml) at −78° C. andthe reaction mixture was stirred at that temperature for 15 min. To thiswas added DMF (1.1 ml) at −78° C. and the reaction mixture was stirredat that temperature for 15 min. The reaction mixture was quenched bysat. NH₄Cl aq. and extracted with ethyl acetate. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give title compound (1.5 g) asbrown solid which was used into the next step without purification.

¹H NMR (400 MHz, DMSO-d₆): δ 1.56 (9H, s), 2.33 (6H, s), 7.62 (2H, s),9.95 (1H, s).

C) tert-butyl 4-[hydroxymethyl]-2,6-dimethylbenzoate

To a stirred solution of tert-butyl 4-formyl-2,6-dimethylbenzoate (3.8g) in methanol (35 ml) was added NaBH₄ (676 mg) slowly portionwise at 0°C., and the reaction mixture was stirred at that temperature for 20 min.After completion of reaction (as judged by TLC), the volatiles wereremoved under reduce pressure. The residue was dissolved in ice coldwater. The aqueous layer was extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude thus obtained was purified by silica gelcolumn chromatography (SiO₂, 40 g, 15% EtOAc/Hexane) to give titlecompound (2.7 g) as colorless oil.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.23 (6H, s), 4.42 (2H, d,J=5.6 Hz), 5.16 (1H, t, J=5.6 Hz), 6.90 (2H, s).

D) tert-butyl 4-[bromomethyl]-2,6-dimethylbenzoate

To a stirred solution of tert-butyl4-[hydroxymethyl]-2,6-dimethylbenzoate (2.8 g) in THF (60 ml) were addedPPh₃ (3.734 g) followed by CBr₄ (5.9 g) at 0° C. and the reactionmixture was stirred at 0° C. for 30 min. After completion of reaction(as judged by TLC), the volatiles were removed under reduced pressure.The crude thus obtained was purified by silica gel column chromatography(SiO₂, 40 g, 12% EtOAc/Hexane) to give title compound (3 g) as whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.23 (6H, s), 4.62 (2H, s),7.15 (2H, s).

E) tert-butyl4-[[3-[5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate

To a stirred solution of3-(5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl)propan-1-ol (7.2 g) inDMF (50 ml) was added NaH (1.28 g) at 0° C. and the reaction mixture wasstirred for 30 min at that temperature. To this was added tert-butyl4-(bromomethyl)-2,6-dimethylbenzoate (8 g) and the reaction mixture wasstirred for another 2.5 h at the same temperature. After completion ofreaction (as judged by TLC and LC/MS), the reaction mixture was quenchedwith ice-water. The aqueous layer was extracted with EtOAc. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude thus obtained waspurified by silica gel column chromatography (SiO₂; 120 g; 30%EtOAc/Hexane) to afford title compound (11 g) as brown oil.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.16-2.21 (8H, m), 2.70 (3H,s), 3.38 (2H, t, J=5.8 Hz), 4.31 (2H, s), 4.77 (2H, t, J=6.6 Hz), 6.89(2H, s), 7.79-7.87 (2H, m). MS m/z 489.3 [M+H]⁺.

F) tert-butyl4-[[3-[5-cyano-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate

To a stirred solution of tert-butyl4-[[3-[5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate(6 g) in DMA (30 mL) were added Zn(CN)₂ (866 mg) and Zn-dust (240 mg) at25° C., and the reaction mixture was degassed with argon atmosphere for10 min. To this was added Pd₂(dba)₃ (563 mg) followed by dppf (681 mg)at 25° C. and the reaction mixture was heated at 150° C. for 6 h. Aftercompletion of reaction (as judged by TLC and LC/MS), the reactionmixture was cooled to 25° C., filtered through celite and washed withEtOAc. The filtrate was diluted with water (10 times) and stirred for 30min. The aqueous layer was extracted with EtOAc. The organic layer waswashed with water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced Pressure. The crude thus obtained waspurified by silica gel column chromatography (SiO₂, 40 g, 20-25%EtOAc/Hexane) to give title compound (3 g) as colorless sticky oil.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.16-2.21 (8H, m), 2.85 (3H,s), 3.41 (2H, t, J=5.8 Hz), 4.26 (2H, s), 4.83 (2H, t, J=6.6 Hz), 6.84(2H, s), 7.78 (1H, d, J=8.7 Hz), 7.93 (1H, d, J=8.7 Hz). MS m/z 435.0[M+H]⁺.

G) tert-butyl4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate

To a stirred solution of tert-butyl4-[[3-[5-cyano-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate(3 g) in mixture of pyridine (120 ml), AcOH (60 ml) and water (60 ml)was added NaPO₂H₂ (6 g) followed by Raney Ni (in water) (15 ml), and thereaction mixture was stirred at 50° C. for 1 h. After completion ofreaction (as judged by TLC and LC/MS), the reaction mixture was filteredthrough celite and washed with EtOAc. Filtrate was diluted with ethylacetate, washed with 0.5M aqueous citric acid, saturated aqueous NaHCO₃,water, and brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude thusobtained was purified by silica gel column chromatography (SiO₂, 40 g,30-35% EtOAc/Hexane) to give title compound (2.1 g) as brown oil.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 2.17-2.20 (8H, m), 3.05 (3H,s), 3.40 (2H, t, J=5.8 Hz), 4.30 (2H, s), 4.81 (2H, t, J=6.6 Hz), 6.88(2H, s), 7.78 (1H, d, J=8.6 Hz), 7.93 (1H, d, J=8.6 Hz), 10.44 (1H, s).MS m/z 438.1 [M+H]⁺.

H) tert-butyl7-[[1-[3-[[4-[[tert-butoxy]carbonyl]-3,5-dimethylphenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl][hydroxy]methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a degassed solution of tert-butyl4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate(700 mg) in mixture of CPME (45 ml) and water (9 ml) was addedtert-butyl7-[tetramethyl-1,3,2-dioxaborolan-2-yl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(1.725 g), followed by K₃PO₄ (1.02 g) and [RhCl(COD)]₂ (158 mg) at 25°C. The reaction mixture was heated at 50° C. for 2 h. The reactionmixture was cooled to 25° C. and quenched with sat NH₄Cl. The aqueouslayer was extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude thus obtained was purified by silica gel columnchromatography (SiO₂, 12g, 25% EtOAc/Hexane) to give title compound (500mg) as light yellow sticky solid.

MS m/z 671.1 [M+H]⁺.

I) tert-butyl7-[1-[1-[3-[[4-[(tert-butoxy]carbonyl]-3,5-dimethylphenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl]-3-methoxy-2,2-dimethyl-3-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a stirred solution of tert-butyl7-[[1-[3-[[4-[[tert-butoxy]carbonyl]-3,5-dimethylphenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl][hydroxy]methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(550 mg) in DCM (30 ml) was added[[1-methoxy-2-methylprop-1-en-1-yl]oxy]trimethylsilane (0.9 ml) followedby TiCl₄ (1M in DCM, 1.8 ml) at −10° C. and the reaction mixture wasstirred at −10° C. for 5 min. After completion of reaction (as jugged byLC/MS and TLC), the reaction mixture was quenched with water. Aqueouslayer was basified with saturated aqueous NaHCO₃ solution (pH˜8) andfiltered through celite bed. The aqueous layer was extracted with 10%MeOH/DCM (3×10 ml), the combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo to give titlecompound (600 mg) as light grey solid, which was used to next stepwithout further purification.

MS m/z 755.6 [M+H]⁺.

J)4-[[3-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoicAcid

To a stirred solution of tert-butyl7-[1-[1-[3-[[4-[[tert-butoxy]carbonyl]-3,5-dimethylphenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl]-3-methoxy-2,2-dimethyl-3-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(1.4 g) in dioxane (14 ml) was added HCl (4M in dioxane, 14 ml) dropwiseat 25° C. and the reaction mixture was stirred at that temperature for 2h. After completion of reaction (as judged by LC/MS), the volatiles wereremoved under reduced pressure and crude thus obtained was purified byreverse phase prep-HPLC (method A) to give title compound (600 mg) asoff white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.24-1.30 (6H, m), 1.61 (6H, s), 2.23-2.25(2H, m), 2.74 (3H, s), 2.90 (2H, brs), 3.13-3.33 (5H, m), 3.42 (5H, s),3.82-3.86 (1H, m), 4.02-4.05 (1H, m), 4.31-4.34 (1H, m), 4.69-4.73 (3H,m), 6.18 (2H, s), 6.73 (1H, s), 7.07 (1H, d, J=7.9 Hz), 7.34 (1H, d,J=7.0 Hz), 7.54 (1H, d, J=8.9 Hz), 7.62 (1H, d, J=8.7 Hz). MS m/z 599.1[M+H]⁺.

K) methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeShort) L) methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeLong)

To a stirred solution of HATU (330.643 mg) in DMF (10 ml) was added amixture of4-[[3-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoicacid (400 mg, 0.669 mmol) and N,N-diisopropylethylamine (0.437 mL, 2.508mmol) in DMF (12 ml) by syringe pump for 1 h at 25° C. and the reactionmixture was stirred at room temperature for 3 h. After completion ofreaction (as judged by LC/MS); reaction mixture was diluted withsaturated NaHCO₃ solution. The aqueous layer was extracted with EtOAc,the combined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and evaporated under reduced pressure. The crude thus obtainedwas purified by normal phase chiral preparative HPLC (method C) toafford methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (retention timeshort) (55 mg) and methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (retention timelong) (60 mg).

methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeShort)

MS m/z 581.0 [M+H]⁺.

methyl2-methyl-2[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoate (Retention TimeLong)

MS m/z 580.9 [M+H]⁺.

M)2-methyl-2[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoicAcid <Chiral, Synthesis from chiral methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8, 9, 10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18,24(28),25,30-decaen-2-yl]propanoate (Retention TimeShort)>

To a stirred solution of methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4, 6, 8,16, 18, 24(28), 25, 30-decaen-2-yl]propanoate (retentiontime short) (121 mg) in DMSO (2.3 ml) was added TMSOK (133.82 mg) at 25°C. and the reaction mixture was heated at 50° C. for 3 h. Aftercompletion of reaction (as jugged by TLC and LC/MS), the reactionmixture was cooled to 25° C. The reaction mixture was diluted with EtOAcand neutralized with 1N HCl. The organic layer was separated and theaqueous layer was extracted with EtOAc. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. This crude thus obtained was purified by reverse phaseprep-HPLC (method A) to give title compound (40 mg) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.15 (3H, s), 1.31 (3H, s), 1.34 (3H, s),1.92 (3H, s), 2.39 (5H, brs), 2.90 (2H, t, J=6.4 Hz), 3.34-3.35 (2H, m),3.52-3.63 (2H, m), 3.98-4.25 (4H, m), 4.68-4.73 (2H, m), 4.80-4.85 (1H,m), 5.84 (1H, s), 5.94 (1H, s), 6.78 (1H, s), 7.15 (1H, d, J=7.9 Hz),7.32-7.38 (2H, m), 7.55 (1H, d, J=8.7 Hz), 12.30 (1H, brs). MS m/z 567.5[M+H]⁺.

Example 592-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoicAcid <Chiral, Synthesis from chiral methyl2-methyl-2-[18,30,32-trimethyl-20-oxo 14-oxa-8, 9, 10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18,24(28),25,30-decaen-2-yl]propanoate (Retention TimeLong)>

To a stirred solution of methyl2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8, 9, 10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6, 8,16,18,24(28),25,30-decaen-2-yl]propanoate (retention timelong) (100 mg) in DMSO (1.8 ml) was added TMSOK (110.59 mg) at 25° C.and the reaction mixture was heated at 50° C. for 3 h. After completionof reaction (as jugged by TLC and LC/MS), the reaction mixture wascooled to 25° C. The reaction mixture was diluted with EtOAc andneutralized with 1N HCl. The aqueous layer was extracted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude thus obtained waspurified by reverse phase prep-HPLC (method A) to give title compound(40 mg) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.15 (3H, s), 1.31 (3H, s), 1.34 (3H, s),1.92 (3H, s), 2.39 (5H, brs), 2.90 (2H, t, J=6.3 Hz), 3.33-3.34 (2H, m),3.52-3.65 (2H, m), 3.98-4.02 (1H, m), 4.09-4.25 (3H, m), 4.66-4.71 (2H,m) 4.80-4.85 (1H, m), 5.83 (1H, s), 5.94 (1H, s), 6.78 (1H, s), 7.15(1H, d, J=7.8 Hz), 7.33 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.8 Hz), 7.55(1H, d, J=8.8 Hz), 12.22 (1H, brs). MS m/z 567.5 [M+H]⁺.

Example 602-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoicAcid <Chiral, Synthesis from chiral methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate(Retention Time Short)>

A) tert-butyl 4-bromo-2,6-dichlorobenzoate

A solution of 4-bromo-2,6-dichlorobenzoic acid (5 g) in toluene (50 mL)was heated to 100° C. for 1 h. To this was added N,N-dimethylformamidedi-tert-butyl acetal (27 mL) in toluene (20 mL) dropwise at heatingcondition and stirred the reaction mixture for another 1 h. Aftercompletion of reaction (as jugged by TLC), the volatiles were evaporatedunder reduced pressure and the crude thus obtained was purified bysilica gel column chromatography (SiO₂, 40 g, 10% EtOAc/Hexane) to givetitle compound (5.6 g) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 7.90 (2H, s).

B) tert-butyl 2,6-dichloro-4-formylbenzoate

To a stirred solution of tert-butyl 4-bromo-2,6-dichlorobenzoate (5.6 g)in THF (100 ml) was added iPrMgBr (2M in THF) (17 ml) at 0° C. and thereaction mixture was stirred at that temperature for another 15 min. Tothis was added DMF (0.6 ml) at 0° C. and stirred the reaction mixture atthat temperature for another 15min. After completion of reaction (asjugged by TLC), the reaction mixture was quenched with sat. aq. NH₄Cl.The aqueous was extracted with EtOAc, combined organics were washed withbrine; dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give title compound (4.6 g) as colorless oil, which was usedto next step without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ1.55 (9H, s), 8.04 (2H, s), 9.97 (1H, s).

C) tert-butyl 2,6-dichloro-4-[hydroxymethyl]benzoate

To a stirred solution of tert-butyl 2,6-dichloro-4-formylbenzoate (4.6g) in methanol (35 ml) was added NaBH₄ (700 mg) slowly portionwise at 0°C., and the reaction mixture was stirred at that temperature for 20 min.After completion of reaction (as judged by TLC), the volatiles wereremoved under reduce pressure. The residue was poured in ice cold water.The aqueous was extracted with EtOAc, combined organics were washed withbrine; dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude thus obtained was purified by silica gel columnchromatography (SiO₂, 40 g, 10% EtOAc/Hexane) to give title compound(3.3 g) as colorless liquid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (9H, s), 4.51 (2H, d, J=5.8 Hz), 5.51(1H, t, J=5.8 Hz), 7.44 (2H, s).

D) tert-butyl 4-(bromomethyl)-2,6-dichlorobenzoate

To a stirred solution of tert-butyl2,6-dichloro-4-[hydroxymethyl]benzoate (3.7g) in THF (45 ml) were addedPPh₃ (8.7 g) followed by NBS (5.24 g) at 0° C. and the reaction mixturewas stirred at 0° C. for 2 h. After completion of reaction (as judged byTLC), the volatiles were removed under reduced pressure. The crude thusobtained was purified by silica gel column chromatography (SiO₂, 40 g,10% EtOAc/Hexane) to give title compound (3.8 g) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.55 (9H, s), 4.69 (2H, s), 7.67 (2H, s).

E) 3-[5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propan-1-ol

To a degassed solution of3-[5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl]propan-1-ol (5 g) inmixture of THF (50 ml) and n-propanol (100 ml) were added potassiumvinyltrifluoroborate (10 g) followed by TEA (10 ml) at 25° C. and thereaction mixture was degassed with argon for 15 min. To this was addedPdCl₂(dppf), DCM (1.5 g) at 25° C. and the reaction mixture was heatedat 100° C. for 2 h. After completion of reaction (as jugged by TLC andLC/MS), the reaction mixture was cooled to 25° C. The volatiles wereremoved under reduced pressure and crude thus obtained was dissolvedwith water. The aqueous layer was extracted with EtOAc, combinedorganics were washed with brine; dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude thus obtained waspurified by silica gel column chromatography (SiO₂, 40 g, 60%EtOAc/Hexane) to give title compound (3.5 g) as brown liquid.

¹H NMR (400 MHz, DMSO-d₆): δ 2.04 (2H, t, J=6.4 Hz), 2.70 (3H, s), 3.38(2H, q, J=5.6 Hz), 4.71 (3H, t, J=7.0 Hz), 5.38 (1H, d, J=11.0 Hz),5.75-5.83 (1H, m), 7.08-7.15 (1H, m), 7.60-7.69 (1H, m), 7.75 (1H, d,J=8.7 Hz). MS m/z 218.0 [M+H]⁺.

F) tert-butyl2,6-dichloro-4-[[3-[5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate

To a stirred solution of3-[5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propan-1-ol (4.5 g) inTHF (100 ml) was added NaH (60% in oil, 2.5 g) at 0° C. and the reactionmixture was stirred at 25° C. for 30 min. To this was added tert-butyl4-[bromomethyl]-2,6-dichlorobenzoate (7 g) at 0° C. and stirred thereaction mixture at 25° C. for 4 h. After completion of reaction (asjudged by TLC and LC/MS), the reaction mixture was quenched withice-water. The aqueous layer was extracted with EtOAc, combined organicswere washed with brine; dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude thus obtained was purified by silicagelcolumn chromatography (SiO₂; 120 g; 10%EtOAc/Hexane) to afford titlecompound (6 g) as brown liquid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.55 (9H, s), 2.15-2.21 (2H, m), 2.68 (3H,s), 3.42 (2H, t, J=5.7 Hz), 4.39 (2H, s), 4.77 (2H, t, J=6.6 Hz),5.36-5.39 (1H, m), 5.77-5.80 (1H, m), 7.07-7.11 (1H, m), 7.34 (2H, s),7.62 (1H, d, J=8.8 Hz), 7.73 (1H, d, J=8.7 Hz). MS m/z 475.8 [M+H]⁺.

G) tert-butyl2,6-dichloro-4-[[3-[5-(hydroxymethyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate

To a stirred solution of tert-butyl2,6-dichloro-4-[[3-[5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate(4.1 g) in DCM (80 ml) was added pyridine (2.08 ml) and cooled to −78°C. To this ozone gas was passed for 10 min at −78° C. After completionof reaction (as jugged by TLC), the reaction mixture was warmed to 25°C. Reaction mixture was diluted with DCM and quenched with 0.5 N citricacid. The aqueous layer was extracted with DCM, combined organics werewashed with brine; dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford in separable mixture of1-[3-[{4-[[tert-butoxy) carbonyl]-3,5-dichlorophenyl} methoxy)propyl]-4-methyl-1H-1,2,3-benzotriazole-5-carboxylic acid and tert-butyl2,6-dichloro-4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy] methyl] benzoate (4 g, crude) as colorless liquid, which wasused to next step without further purification.

To a solution of 1-[3-[[4-[[tert-butoxy] carbonyl]-3,5-dichlorophenyl]methoxy] propyl]-4-methyl-1H-1,2,3-benzotriazole-5-carboxylic acid andtert-butyl2,6-dichloro-4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy] methyl] benzoate (4.6 g) in THF (50 ml) were successively addedNMM (1.5 ml) followed by isobutyl chloroformate (2.4 ml) at −15° C. andthe reaction mixture was stirred for 10 min at that temperature. Aftercompletion of reaction (as jugged by TLC), the reaction mixture wasfiltered and the precipitate was washed with THF (2×50 ml). To this wasadded NaBH₄ (1.4 g) in water (10 ml) at −15° C. in one portion and thereaction mixture was stirred at that temperature for 5 min. Aftercompletion of starting (as judged by TLC), water (125 ml) was added. Theaqueous layer was extracted with DCM, combined organics were washed withbrine; dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude thus obtained was purified by silica gel columnchromatography (SiO₂; 40 g; 40% EtOAc/Hexane) to afford title compound(1.9 g) as colorless liquid.

MS m/z 479.7 [M+H]⁺.

H) tert-butyl2,6-dichloro-4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate

To a stirred solution of tert-butyl2,6-dichloro-4-[[3-[5-[hydroxymethyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate(1.9 g) in DCM (50 ml) was added active MnO₂ (6 g) at 25° C. and thereaction mixture was stirred at 25° C. for 4 h. After completion ofreaction (as jugged by TLC), the insoluble material was filtered throughcelite bed. Filtrate was evaporated under reduced pressure to give titlecompound (1.7 g) as brown liquid, which was used to next step withoutfurther purification.

¹H NMR (400 MHz, DMSO-d₆): δ 1.55 s), 2.19-2.25 (2H, m), 3.02 (3H, s),3.47 (2H, t, J=5.7 Hz), 4.33 (2H, s), 4.83 (2H, t, J=6.4 Hz), 7.24 (2H,s), 7.80 (1H, d, J=8.6 Hz), 7.92 (1H, d, J=8.6 Hz), 10.42 (1H, s). MSm/z 477.9 [M+H]⁺.

I) tert-butyl7-[[1-(3-[[3,5-dichloro-4-[methoxycarbonyl]phenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl][hydroxy]methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a degassed solution of tert-butyl2,6-dichloro-4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate(1.2 g) in mixture of CPME (50 ml) and water (10 ml) were addedtert-butyl7-[tetramethyl-1,3,2-dioxaborolan-2-yl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(2.7 g) followed by K₃PO₄ (1.6 g) at 25° C. To this was added[RhCl(COD)]₂ (627 mg) at 25° C. and reaction mixture was heated at 50°C. for 2 h. TLC and LC/MS of reaction mixture showed formation ofdesired product along with un-reacted starting material. The reactionmixture was cooled to 25° C. and quenched with sat. aq. NH₄Cl. Theaqueous layer was extracted with EtOAc, combined organics were washedwith water, brine, dried over anhydrous Na₂SO₄, filtered and filtratewas concentrated under reduced pressure. The crude thus obtained waspurified by silica gel column chromatography (SiO₂, 12 g, 25%EtOAc/Hexane) to give title compound (800 mg) as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ1.40 (9H, s), 1.55 (9H, s), 2.18 (2H, t,J=5.8 Hz), 2.69-2.74 (5H, m), 3.42-3.50 (4H, m), 4.36-4.42 (4H, m), 4.74(2H, t, J=6.1 Hz), 5.86 (1H, d, J=3.4 Hz), 6.03 (1H, d, J=3.7 Hz),7.04-7.13 (3H, m), 7.41 (2H, s), 7.59 (2H, s). MS m/z 711.2 [M+H]⁺.

J) tert-butyl2,6-dichloro-4-[[3-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate

To a stirred solution of tert-butyl7-[[1-(3-[[3,5-dichloro-4-[methoxycarbonyl] phenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl][hydroxy]methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(970 mg)) in DCM (30 mL) were added[(1-methoxy-2-methylprop-1-en-1-yl)oxy]trimethylsilane (1.5 ml) followedby TiCl₄ (1M in DCM, 3 ml) at 0° C. and the reaction mixture was stirredat that temperature for 5 min. After completion of reaction (as juggedby LC/MS and TLC), the reaction mixture was quenched with water. Aqueouslayer was basified with saturated NaHCO₃ solution (pH˜8) and filteredthrough celite bed. After filtration, aqueous layer was extracted with10% MeOH/DCM (3×50 mL), the combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and evaporated to give title compound(1 g, crude) as colorless liquid, which was used to next step withoutfurther purification.

MS m/z 795.3[M+H]⁺.

K)2,6-dichloro-4-[[3-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoicAcid

To a stirred solution of tert-butyl2,6-dichloro-4-[[3-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate (970 mg) in dioxane (10 mL) was added HCl (4M in dioxane, 10mL) dropwise at 25° C. and the reaction mixture was stirred at thattemperature for 2 h. After completion of reaction (as judged by LC/MS),the volatiles were removed under reduced pressure and crude thusobtained was purified by reverse phase prep-HPLC (method A) to givetitle compound (250 mg) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.26-1.30 (6H, m), 2.25-2.29 (2H, m), 2.78(3H, s), 2.90-2.92 (2H, m), 3.13-3.28 (4H, m), 3.39-3.41 (1H, m), 3.43(3H, s), 3.82-3.87 (1H, m), 4.04-4.13 (2H, m), 4.34-4.38 (1H, m),4.63-4.68 (1H, m), 4.74-4.79 (2H, m), 6.71 (2H, s), 6.98 (1H, s), 7.03(1H, d, J=8.0 Hz), 7.32 (1H, d, J=7.5 Hz), 7.54 (1H, d, J=8.8 Hz), 7.59(1H, d, J=8.6 Hz), 10.10 (1H, brs). MS m/z 638.6 [M+H]⁺.

L) methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]-dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate (Retention Time Short)

M) methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate (Retention Time Long)

To a solution of HATU (293 mg) in DMF (15 ml) was added a mixture of2,6-dichloro-4-[[3-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoicacid (380 mg) and N,N-diisopropylethylamine (0.5 ml) in DMF, (20 ml) at25° C. by syringe pump for 1 h and the reaction mixture was stirred atthat temperature for 3 h. After completion of reaction (as judged byLC/MS); reaction mixture was diluted with saturated NaHCO₃ solution. Theaqueous layer was extracted with EtOAc, the combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to give methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate(racemate, 250 mg, crude) as white solid.

The crude thus obtained was purified by normal phase chiral HPLC (methodC) to afford methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate (retention time short) (55mg) and methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25, 30-decaen-2-yl]-2-methylpropanoate (retention time long) (45mg) as white solid.

methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]-2-methylpropanoate(Retention Time Short)

¹H NMR (400 MHz, DMSO-d₆): δ 1.23-1.27 (6H, m), 1.32 (3H, s), 2.19-2.52(5H, m), 2.89-2.92 (2H, m), 3.39-3.40 (2H, m), 3.61-3.70 (2H, m),4.01-4.09 (2H, m), 4.22-4.34 (2H, m), 4.72-4.80 (3H, m), 5.98 (1H, s),6.31 (1H, s), 7.12 (1H, d, J=7.6 Hz), 7.24-7.29 (3H, m), 7.55 (1H, d,J=8.7 Hz). MS m/z 621.0 [M+H]⁺.

methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]-2-methylpropanoate(Retention Time Long)

¹H NMR (400 MHz, DMSO-d₆): δ 1.17-1.30 (6H, m), 1.32 (3H, s), 2.19-2.52(5H, m), 2.90-2.92 (2H, m), 3.39-3.40 (2H, m), 3.57-3.68 (2H, m),4.01-4.09 (2H, m), 4.22-4.34 (2H, m), 4.72-4.80 (3H, m), 5.98 (1H, s),6.31 (1H, s), 7.12 (1H, d, J=8.1 Hz), 7.24-7.29 (3H, m), 7.55 (1H, d,J=9.0 Hz). MS m/z 621.0 [M+H]⁺.

N)2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoicAcid <Chiral, Synthesis from chiral methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate (Retention TimeShort)>

To a stirred solution of methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate (retention timeshort) (100 mg) in mixture of DMSO (2 ml) and MeOH (2 ml) was addedaqueous KOH (8N, 1 ml) at 25° C. and the reaction mixture was heated at100° C. for 3 h. After completion of reaction (as jugged by LC/MS), thereaction mixture was cooled to 25° C. The reaction mixture was dilutedwith EtOAc and neutralized with 1N HCl. The aqueous layer was extractedwith EtOAc, the combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crude thusobtained was purified by reverse phase prep-HPLC (method A) to givetitle compound (32.65 mg) as off white sticky solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.15-1.30 (6H, m), 2.38-2.50 (5H, m), 2.91(2H, t, J=6.5 Hz), 3.29-3.42 (2H, m), 3.58-3.62 (1H, m), 3.69-3.72 (1H,m), 3.99-4.07 (2H, m), 4.22-4.35 (2H, m), 4.71-4.82 (3H, m), 5.95 s),6.34 (1H, s), 7.12 (1H, d, J=7.9 Hz), 7.28-7.36 (3H, m), 7.55 (1H, d,J=8.7 Hz), 12.30 (1H, brs). MS m/z 607.5 [M+H]⁺.

Example 612-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoicAcid <Chiral, Synthesis from chiral methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32), 4,6, 8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate(Retention Time Long)>

To a stirred solution of methyl2-[18,30-dichloro-32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate (retention time long)(100 mg) in mixture of DMSO (2 ml) and MeOH (2 ml) was added KOH (8N, 1ml) at 25° C. and the reaction mixture was heated at 100° C. for 3 h.After completion of reaction (as jugged by LC/MS), the reaction mixturewas cooled to 25° C. The reaction mixture was diluted with EtOAc andneutralized with 1N HCl. The aqueous layer was extracted with EtOAc, thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and evaporated under reduced pressure. The crude thus obtainedwas purified by reverse phase prep-HPLC (method A) to give titlecompound (22.16 mg) as off white sticky solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.14-1.33 (6H, m), 2.32-2.42 (5H, m), 2.90(2H, t, J=6.2 Hz), 3.31-3.41 (2H, m), 3.58-3.62 (1H, m), 3.67-3.63 (1H,m), 3.98-4.06 (2H, m), 4.22-4.34 (2H, m), 4.70-4.81 (3H, m), 5.95 (1H,s), 6.34 (1H, s), 7.12 (1H, d, J=7.8 Hz), 7.28-7.36 (3H, m), 7.55 (1H,d, J=8.7 Hz), 12.27 (1H, brs). MS m/z 607.5 [M+H]⁺.

Example 62 2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoicAcid <Chiral, Synthesis from chiral methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoate(Retention Time Short)>

A) tert-butyl4-[5-[4-methyl-5-vinyl-1H-benzo[d][1,2,3]triazol-1-yl]pentyl]benzoate

A solution of potassium vinyltrifluoroborate (1.50 g,),PdCl₂(dppf)-CH₂Cl₂ (0.28 g), tert-Butyl4-[5-(5-bromo-4-methyl-1H-benzotriazol-1-yl)pentyl]benzoate (3.50 g) andK₂CO₃ (3.10 g) in DMSO (35 mL) was heated to 80° C. for 16 h. After thereaction was completed, the reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, filtrated through a celite pad.The filtrate was washed with water followed by brine and dried overanhydrous Na₂SO₄. Na₂SO₄ was filtered off and the filtrate wasconcentrated in vacuo. The crude obtained was purified by flashchromatography, using 40 g Redisep silica gel cartridge, on a silica gelchromatography instrument, eluted with 20-50% gradient of ethyl acetatein hexanes, to obtain title compound (2.50 g) as brown oil. ¹H NMR (400MHz, DMSO-d₆) δ 1.34-1.42 (2H, m), 1.58 (9H, m), 1.62-1.70 (2H, m),1.86-2.04 (2H, m), 2.61 (2H, t, J=7.2 Hz), 2.82 (3H, s), 4.59 (2H, t,J=6.8 Hz), 5.40 (1H, t, J=11.2 Hz), 5.71 (1H, t, J=17.6 Hz), 7.07-7.11(1H, m), 7.16 (2H, t, J=8.0 Hz), 7.26-7.29 (1H, m), 7.66 (1H, t, J=8.8Hz), 7.87 (2H, t, J=8.0 Hz). MS m/z 406.15 [M+H]⁺.

B) tert-butyl4-[5-[5-formyl-4-methyl-1H-benzo[d][1,2,3]triazol-1-yl)pentyl)benzoate

To a solution of tert-butyl4-[5-[4-methyl-5-vinyl-1H-benzo[d][1,2,3]triazol-1-yl]pentyl]benzoate(3.40 g) in 1,4-dioxane (100 mL) were added 2,6-lutidine (1.50 g, 14.70mmol) and OsO₄ (0.21 g, 0.84 mmol), and the mixture was stirred at roomtemperature for 20 min. To that mixture, a solution of NaIO₄ (6.30 g,29.40 mmol) in water (25 mL) was added and stirring continued at roomtemperature for 2 h. After the reaction was completed, reaction mixturewas filtrated through celite, and the filtrate was extracted with ethylacetate. The organic extract was dried over Na₂SO₄, filtered and solventevaporated from the filtrate under reduced pressure. The crude obtainedwas purified by flash chromatography, using 40 g Redisep silica gelcartridge, on a silica gel chromatography instrument, eluted with 20-50%gradient of ethyl acetate in hexanes, to obtain title compound (3.00 g)as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.17-1.23 (2H, m), 1.52(9H, s), 1.56-1.61 (2H, m), 1.90-1.97 (2H, m), 2.57 (2H, t, J=7.5 Hz),3.06 (3H, s), 4.72 (2H, t, J=6.8 Hz), 7.20 (2H, d, J=8.0 Hz), 7.73 (2H,d, J=8.0 Hz), 7.81 (1H, d, J=8.7 Hz), 7.94 (1H, d, J=8.7 Hz), 10.44 (1H,s). MS: purity m/z 408.24 [M+H]⁺.

C) tert-butyl7-[[1-[5-[4-[tert-butoxycarbonyl]phenyl]pentyl]-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl][hydroxy]methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl4-[5-[5-formyl-4-methyl-1H-benzo[d][1,2,3]triazol-1-yl]pentyl]benzoate(0.50 g) and tripotassium phosphate (0.78 g) in CPME (30 mL) and water(6 ml),7-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.30 g) and chloro[1,5-cyclooctadiene]rhodium(I) dimer (0.21 g) wereadded, under argon atmosphere and the mixture was stirred at roomtemperature for 16 h. After completion of the reaction, the mixture wasdiluted with sat. NH₄Cl aq. and extracted with ethyl acetate. Theorganic extract was washed with brine, dried over anhydrous Na₂SO₄,filtered and solvents evaporated from the filtrate under reducedpressure. The crude obtained was purified by flash chromatography, using12 g Redisep silica gel cartridge, on a silica gel chromatographyinstrument, eluted with 20-70% gradient of ethyl acetate in hexanes, toobtain title compound (0.25 g) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ1.04-1.13 (2H, m), 1.47 (9H, s), 1.58-1.74 (11H, m), 1.74-1.84(2H, m), 2.00-2.04 (2H, m), 2.59-2.62 (2H, m), 2.80 (3H, s), 2.46-2.53(2H, m), 2.80 (2H, brs), 3.62-3.66 (2H, m), 4.52 (1H, s), 4.59-4.61 (1H,m), 6.25 (1H, s), 7.04-7.12 (4H, m), 7.26 (1H, s), 7.65 (1H, d, J=8.2Hz), 7.81 (2H, d, J=7.9 Hz). MS m/z 641.46 [M+H⁺].

D)4-[5-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl)propyl]-4-methyl-1H-benzo[d][1,2,3]triazol-1-yl]pentyl]benzoic Acid hydrochloride

To a stirred solution of tert-butyl7-[[1-[5-[4-[tert-butoxycarbonyl]phenyl]pentyl]-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl][hydroxy]methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.35 g) in DCM (14 mL),[[1-methoxy-2-methylprop-1-en-1-yl]oxy]trimethylsilane (0.57 g) andTiCl₄ (1M in DCM, 0.54 mL) were added at 0° C. and the reaction mixturewas stirred for 5 min. After completion of reaction (as jugged by LCMSand TLC), the reaction mixture was quenched with water. Aqueous layerwas basified with saturated NaHCO₃ solution (pH˜8) and filtered throughcelite pad. After filtration aqueous layer was extracted with 10%methanol in dichloromethane. The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄, filtered and solvent evaporatedfrom the filtrate to obtain a mixture (0.43 g) as light grey solid,which was used as such in the next step. To a mixture in 1,4-dioxane (5mL) was added 4M HCl in 1,4-dioxane (6 mL) dropwise at 25° C. and thereaction mixture was stirred for 6 h. After completion of reaction (asjudged by LCMS), the volatiles were removed under reduced pressure toobtain title compound (0.40 g, crude) as a grey solid, which was used assuch in the next step.

MS m/z 569.43 [M+H ⁺].

E) methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoate

To a solution of HATU (0.66 g, 1.75 mmol) in DMF (10 ml) was added amixture of4-[5-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-benzo[d][1,2,3]triazol-1-yl]pentyl]benzoicacid (0.4 g, crude) and N,N-diisopropylethylamine (2.3 g, 17.6 mmol) inDMF (30 ml) by syringe pump for 3 h at 30° C. and the reaction mixturewas stirred at room temperature for 16 h. After completion of reaction(as judged by LCMS); reaction mixture was diluted with saturated NaHCO₃solution. The aqueous layer was extracted with ethyl acetate. Thecombined organic extract was washed with brine, dried over anhydrousNa₂SO₄, filtered and solvents evaporated from the filtrate under reducedpressure. The crude obtained was purified by flash chromatography, using12 g Redisep silica gel cartridge, on a silica gel chromatographyinstrument, eluted with 20-60% gradient of ethyl acetate in hexane, toobtain title compound (0.048 g) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ1.03-1.06 (2H, m), 1.28-1.36 (5H, m), 1.45 (3H, s), 2.07 (2H,brs), 2.56-2.59 (2H, m), 2.65 (3H, m), 2.90-2.99 (2H, m), 3.56 (3H, s),3.74-3.79 (1H, m), 4.03-4.07 (1H, m), 4.14-4.18 (2H, m), 4.38-4.42 (1H,m), 4.87 (1H, s), 4.90-4.95 (1H, m), 6.01 (1H, s), 6.80 (2H, d, J=7.7Hz), 6.95 (2H, d, J=7.7 Hz), 7.08-7.09 (1H, m), 7.18 (2H, d, J=8.6 Hz),7.39 (1H, d, J=8.7 Hz). MS m/z 551.31 [M+H⁺].

F) 2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoicacid <Synthesis from chiral methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl)propanoate(Retention Time Short)>

methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoate(racemate) was subjected to chiral HPLC purification (method D) toobtain chiral methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoate(retention time short) and chiral methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazhexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoate(retention time long), which were individually taken forward to the nextstep.

To a solution of chiral methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoate(retention time short, 0.080 g) in THF (8 ml), TMSOK (0.37 g) was addedat room temperature and the mixture was stirred at 60° C. for 16 h. Themixture was, then, cooled to room temperature, diluted with ethylacetate, neutralized with 1N HCl, and extracted with ethyl acetate. Thecombined organic extract was washed with water and brine, dried overanhydrous Na₂SO₄, filtered and solvent evaporated from the filtrateunder reduced pressure. The residue was purified by using preparativeTLC to obtain title compound (0.028 g) as white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.05-1.12 (2H, m), 1.29 (3H, s), 1.48 (3H, s), 1.64 (1H,brs), 2.07 (2H, brs), 2.51-2.58 (2H, m), 2.65 (3H, s), 2.89-2.99 (2H,m), 3.74-3.78 (2H, m), 4.03-4.18 (3H, m), 4.38-4.42 (1H, m), 4.88-4.95(2H, m), 6.01 (1H, s), 6.80 (21-1, d, J=7.6 Hz), 6.95 (2H, d, J=7.6 Hz),7.08 (1H, d, J=7.8 Hz), 7.18-7.26 (2H, m), 7.44 (1H, d, J=8.6 Hz). MSm/z 537.30 [M+H⁺].

Example 632-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoicAcid <Chiral, Synthesis from chiral methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,(31),24(28),25-decaen-2-yl]propanoate(Retention Time Long)>

To a solution of chiral methyl2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoate(retention time long) (0.070 g) in THF (8 ml) TMSOK (0.32 g, 2.50 mmol)was added at room temperature and the mixture was stirred at 60° C. for16 h. The mixture was, then, cooled to room temperature, diluted withethyl acetate, neutralized with 1N HCl, and extracted with ethylacetate. The combined organic extract was washed with water and brine,dried over anhydrous Na₂SO₄, filtered and solvent evaporated from thefiltrate under reduced pressure. The residue was purified by usingpreparative TLC to obtain title compound (0.020 g) as white solid.

¹H NMR (400 MHz, CDCl₃) δ1.05-1.12 (2H, m), 1.29 (3H, s), 1.48 (3H, s),1.64 (1H, brs), 2.07 (2H, brs), 2.51-2.58 (2H, m), 2.65 (3H, s),2.88-2.98 (2H, m), 3.73-3.77 (2H, m), 4.03-4.18 (3H, m), 4.38-4.42 (1H,m), 4.88-4.94 (2H, m), 6.01 (1H, s), 6.80 (2H, d, J=7.6 Hz), 6.95 (2H,d, J=7.6 Hz), 7.08 (1H, d, J=7.8 Hz), 7.18-7.26 (2H, m), 7.44 (1H, d,J=8.6 Hz). MS m/z 537.37 [M+H⁺].

Example 64[2-[18,30-dichloro-32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]acetyl]oxysodium

The compounds of Examples 64 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 652-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]-2-methylpropanoicAcid (Chiral, Retention Time Short)

A) 4-[[4-bromo-3-methyl-2-nitrophenyl]amino]butan-1-ol

To a solution of 1-bromo-4-fluoro-2-methyl-3-nitrobenzene (33 g) in DMF(450 mL) were added K₂CO₃ (39.259 g) followed by 4-amino butanol (17.162ml) at 25° C. and the mixture was stirred at 80° C. for 16 h. Aftercompletion of reaction (as jugged by TLC and LC/MS), the reactionmixture was quenched with ice-cold water. The precipitate thus formedwas filtrated and washed with water and finally dried under high vacuumto afford title compound (40 g) as orange solid, which was used to nextstep without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 1.43-1.53 (4H, m), 2.24 (3H, s), 3.12 (2H,d, J=5.7 Hz), 3.39 (2H, s), 4.40 (1H, s), 6.13 (1H, s), 6.72 (1H, d,J=8.9 Hz), 7.52 (1H, d, J=8.9 Hz).

B) 4-[[2-amino-4-bromo-3-methylphenyl]amino]butan-1-ol

To a stirred solution of4-[[4-bromo-3-methyl-2-nitrophenyl]amino]butan-1-ol (23 g) in a mixtureof ethanol (230 ml) and water (115 m) were added iron powered (21.197 g)followed by NH₄Cl (40.299 g) at 25° C. and reaction mixture was refluxedfor 4 h. After completion of reaction (as jugged by TLC), the insolublematerial was filtered through celite bed and solvent was evaporatedunder reduced pressure. Residue was dissolved in sat NaHCO₃ soln. Theaqueous layer was extracted with ethyl acetate (50 ml×3), the combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to afford title compound (11.8 g) asbrown solid, which was used to next step without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 1.48-1.63 (4H, m), 2.16 (3H, s), 2.96 (2H,q, J=6.4 Hz), 3.40 (2H, q, J=6.0 Hz), 4.40 (1H, t, J=5.0 Hz), 4.53 (1H,t, J=4.9 Hz), 4.59 (2H, s), 6.24 (1H, d, J=8.5 Hz), 6.70 (1H, d, J=8.4Hz). MS m/z 275.1 [M+H]⁺.

C) 4-[5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl]butan-1-ol

To a stirred solution of4-[[2-amino-4-bromo-3-methylphenyl]amino]butan-1-ol (20 g) in 6N HCl(265 mL) was slowly added a solution of NaNO₂ (10.11 g) in water (87 mL)at 0° C. and the reaction mixture was stirred at 25° C. for 2 h. Aftercompletion of reaction (as jugged by TLC and LC/MS), the reactionmixture was neutralized with 4N NaOH at 0° C. The aqueous layer wasextracted with EtOAc, combined organics were washed with brine; driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudethus obtained was purified by silica gel column (SiO₂, 120 g, 60%EtOAc/Hexane) to title compound (14 g) as brown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.32-1.40 (2H, m), 1.88-1.96 (2H, m), 2.71(3H, s), 3.38 (2H, t, J=6.3 Hz), 4.70 (2H, t, J=7.0 Hz), 7.69 (2H, t,J=8.9 Hz). MS m/z 286.1 [M+H]⁺.

D) 4-(5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl)butan-1-ol

To a degassed solution of4-[5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl]butan-1-ol (5 g) inmixture of THF (50 ml) and n-propanol (100 ml) were added potassiumvinyltrifluoroborate (9 g) followed by TEA (10 ml, 70.423 mmol) at 25°C. and the reaction mixture was degassed with argon for 10 min. To thiswas added PdCl₂(dppf)-DCM (1.5 g) and the reaction mixture was heated at100° C. for 2 h. After completion of reaction (as jugged by LC/MS), thevolatiles were removed under reduced pressure. The residue was dissolvedwith water, the aqueous layer was extracted with EtOAc, combinedorganics were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude thus obtained waspurified by silica gel column chromatography (SiO₂, 40 g, 60%EtOAc/Hexane) to give title compound (3 g) as brown liquid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.33-1.40 (2H, m), 1.88-1.96 (2H, m), 2.70(3H, s), 3.36 (2H, q, J=5.9 Hz), 4.43 (1H, t, J=4.9 Hz), 4.68 (2H, t,J=6.9 Hz), 5.38 (1H, d, J=11.2 Hz), 5.81 (1H, d, J=17.4 Hz), 7.08 (1H,q, J=11.1 Hz), 7.68 (1H, t, J=8.7 Hz), 7.75 (1H, d, J=8.6 Hz). MS m/z232.0 [M+H]⁺.

E) tert-butyl2,6-dichloro-4-[4-(5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl)butoxy]benzoate

To a stirred solution of4-[5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]butan-1-ol (3 g) in THF(40 ml) were added tert-butyl 2,6-dichloro-4-hydroxybenzoate (3.4 g) andPPh₃ (8.5 g) at 25° C. To this was added DEAD (4 ml) in THF (10 ml) at0° C. and the reaction mixture was stirred at 25° C. for 3 h. Aftercompletion of reaction (as jugged by TLC and LC/MS), the volatiles wereremoved under reduced pressure. The crude thus obtained was purified bysilica gel column chromatography (SiO₂, 40 g, 20% EtOAc/Hexane) to givetitle compound (4.9 g) as colorless liquid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.53 (9H, s), 1.65-1.70 (2H, m), 2.05-2.03(2H, m), 2.70 (3H, s), 4.04 (2H, t, J=6.2 Hz), 4.75 (2H, t, J=6.8 Hz),5.38 (1H, d, J=11.9 Hz), 5.76-5.83 (2H, m), 7.06-7.08 (1H, m), 7.10-7.15(1H, m), 7.69 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=9.4 Hz). MS m/z 276.0[M+H]⁺.

F) tert-butyl2,6-dichloro-4-[4-[5-(hydroxymethyl)-4-methyl-1H-1,2,3-benzotriazol-1-yl]butoxy]benzoate

To a stirred solution of tert-butyl2,6-dichloro-4-[4-[5-ethenyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]butoxy]benzoate(5 g) in mixture of MeOH (50 ml) and DCM (50 ml) was added NaHCO₃ (1.1g) at 25° C. To this, ozone gas was passed at −78° C. for 2 h. Aftercompletion of reaction (as judged by TLC), the reaction mixture waswarmed to 0° C. To this was added NaBH₄ (0.796 g) at 0° C. and thereaction mixture was stirred at that temperature for 1 h. Aftercompletion of the reaction (as jugged by TLC), the volatiles wereremoved under reduced pressure. The residue was diluted with ice coldwater. The aqueous layer was extracted with DCM, combined organics werewashed with brine; dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude thus obtained was purified by silica gelcolumn (SiO₂, 12 g, 30% EtOAc/Hexane) to give title compound (3.5 g) ascolorless sticky liquid. NMR (400 MHz, DMSO-d₆) δ 1.53 (9H, s),1.66-1.69 (2H, m), 2.03 (2H, t, J=7.2 Hz), 2.64 (3H, s), 4.03 (2H, t,J=6.3 Hz), 4.63 (2H, d, J=5.4 Hz), 4.74 (2H, t, J=6.8 Hz), 5.13 (1H, t,J=5.3 Hz), 7.06 (2H, s), 7.55 (1H, d, J=8.5 Hz), 7.65 (1H, d, J=8.4 Hz).MS m/z 480.1 [M+H]⁺.

G) tert-butyl2,6-dichloro-4-[4-(5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl)butoxy]benzoate

To a stirred solution of tert-butyl2,6-dichloro-4-[4-[5-(hydroxymethyl)-4-methyl-1H-1,2,3-benzotriazol-1-yl]butoxy]benzoate(3.3 g) in DCM (50 ml) was added activated MnO₂ (10 g) at 25° C. and thereaction mixture was stirred at 25° C. for 4 h. After completion ofstarting (jugged by TLC), the insoluble material was filtered throughcelite bed and residue was dissolved with DCM. Filtrate was evaporatedunder reduced pressure to give title (3 g) as off white solid, which wasused to next step without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 1.53 (9H, s), 1.71 (2H, t, J=7.2 Hz), 2.07(2H, t, J=7.6 Hz), 3.06 (3H, s), 4.03 (2H, t, J=6.4 Hz), 4.81 (2H, t,J=6.7 Hz), 7.02 (2H, s), 7.86 (1H, d, J=8.7 Hz), 7.97 (1H, d, J=8.6 Hz),10.45 (1H, s). MS m/z 478.4 [M+H]⁺.

H) tert-butyl7-[[1-[4-[4-[[tert-butoxy]carbonyl]-3,5-dichlorophenoxy]butyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl][hydroxy]methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a degassed solution of tert-butyl2,6-dichloro-4-[4-(5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl)butoxy]benzoate(360 mg) in mixture of CPME (10 ml) and water (5 ml) were added[2-[[tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]boronicacid (627 mg) followed by K₃PO₄ (480 mg) at 25° C. To this was added[RhCl(COD)]₂ (74 mg) at 25° C. and reaction mixture was stirred at 25°C. for 4 h under blue LED light. The reaction mixture was quenched withsat NH₄Cl. The aqueous layer was extracted with EtOAc, combined organicswere washed with water, brine, dried over anhydrous Na₂SO₄, filtered andfiltrate was concentrated under reduced pressure. The crude thusobtained was purified by silica gel column chromatography (SiO₂, 12 g,25% EtOAc/Hexane) to give title compound (300 mg) as light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.40 (9H, s), 1.52 (9H, s), 1.67 (2H, t,J=6.8 Hz), 2.01 (2H, t, J=7.3 Hz), 2.65-2.71 (5H, m), 3.50 (2H, t, J=5.7Hz), 4.06 (2H, t, J=8.0 Hz), 4.43 (2H, s), 4.72 (2H, t, J=6.7 Hz), 5.86(1H, d, J=4.0 Hz), 6.03 (1H, d, J=4.0 Hz), 7.06-7.13 (5H, m), 7.59 (2H,q, J=8.6 Hz). MS m/z 711.6 [M+H]⁺.

I) tert-butyl7-[1-[1-[4-[4-[[tert-butoxy]carbonyl]-3,5-dichlorophenoxy]butyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl]-3-methoxy-2,2-dimethyl-3-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a stirred solution of tert-butyl7-[[1-[4-[4-[[tert-butoxy]carbonyl]-3,5-dichlorophenoxy]butyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl][hydroxy]methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.2 g) in DCM (100ml) were added [[1-methoxy-2-methylprop-1-en-1-yl]oxy]trimethylsilane(1.8 ml) followed by TiCl₄ (1M in DCM, 3.7 ml) at 0° C. and the reactionmixture was stirred at 0° C. for 5 min. After completion of reaction (asjugged by LCMS and TLC), the reaction mixture was quenched with water.Aqueous layer was basified with saturated NaHCO₃ solution (pH˜8) andfiltered through celite bed. The aqueous layer was extracted with 10%MeOH/DCM (3×50 mL), the combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive a compound (1 g, crude) as light grey solid, which was used to nextstep without further purification.

MS m/z 795.8 [M+H]⁺.

J)2,6-dichloro-4-(4-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]butoxy)benzoicAcid

To a stirred solution of tert-butyl7-[1-[1-[4-[4-[[tert-butoxy]carbonyl]-3,5-dichlorophenoxy]butyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl]-3-methoxy-2,2-dimethyl-3-oxopropyl]-1,2, 3, 4-tetrahydro isoquinoline-2-carboxylate (1.3 g, crude) in dioxane(13 ml) was added HCl (4M in dioxane, 13 ml) dropwise at 25° C. and thereaction mixture was stirred at that temperature for 2 h. Aftercompletion of reaction (as judged by LC/MS), the volatiles were removedunder reduced pressure and crude thus obtained was purified by reversephase prep-HPLC (method A) to give title compound (320 mg) as whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.03 (3H, d, J=5.9 Hz), 1.27 (6H, d, J=21.0Hz), 1.50-1.60 (2H, m), 2.03 (2H, t, J=6.1 Hz), 2.73 (3H, s), 3.22-3.25(2H, m), 3.43 (3H, s), 3.83-3.93 (3H, m), 4.70-4.75 (3H, m), 6.62 (2H,s), 6.98 (1H, s), 7.07 (1H, d, J=7.8 Hz), 7.27 (1H, d, J=7.7 Hz), 7.58(1H, d, J=7.5 Hz), 7.65 (1H, d, J=8.7 Hz), 9.70-9.80 (1H, m). MS m/z639.4 [M+H]⁺.

K) methyl2-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta1(27),(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoate

To a solution of HATU (301 mg) in DMF (10 ml) was added a mixture of2,6-dichloro-4-[4-[5-[3-methoxy-2,2-dimethyl-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]butoxy]benzoicacid (390 mg) and N,N-diisopropylethylamine (0.5 ml) in DMF (30 ml) bysyringe pump within 1 h at 25° C. and the reaction mixture was stirredat that temperature for 3 h. After completion of reaction (as judged byLC/MS); reaction mixture was diluted with saturated NaHCO₃ solution. Theaqueous layer was extracted with EtOAc, the combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and evaporated underreduced pressure. The crude thus obtained was purified by triturating togive title compound (180 mg) as off white solid which was used to nextstep without further purification. MS m/z 621.1 [M+H]⁺.

L)2-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]-2-methylpropanoicAcid (Chiral, Retention Time Short)

To a stirred solution of methyl2-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriacontal(27),(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methyl propanoate (180 mg) inmixture of DMSO (4 ml) and MeOH (4 ml) was added KOH (8N, 2 ml) at 25°C. and the reaction mixture was heated at 100° C. for 16 h. Aftercompletion of reaction (as jugged by LC/MS), the reaction mass wascooled to 25° C. and the mixture was diluted with EtOAc. The reactionmixture was acidified with 1N HCl (pH˜4-5). The aqueous layer wasextracted with EtOAc, the combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. Thecrude thus obtained was purified by reverse phase chiral prep-HPLC(method B) to give2-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoic acid (chiral,retention time short, 27.06 mg) as off white sticky solid and2[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoicacid (chiral retention time long, 57.59 mg) as off white sticky solid.

2-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoic Acid (chiral,Retention Time Short)

¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (3H, s), 1.33 (3H, s), 1.51-1.60 (2H,m), 2.07 (2H, q, J=6.2 Hz), 2.56 (3H, s), 2.88-2.90 (2H, m), 3.57-3.76(3H, m), 3.96-4.64 (3H, m), 4.65-4.70 (1H, m), 4.84-5.10 (2H, m), 6.16(1H, s), 6.20 (1H, s), 6.90 (1H, s), 7.09 (1H, d, J=7.8 Hz), 7.29 (1H,d, J=7.4 Hz), 7.51 (1H, d, J=8.7 Hz), 7.57 (1H, d, J=8.6 Hz),11.50-11.60 (1H, m). MS m/z 607.5 [M+H]⁺.

2-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]-2-methylpropanoic Acid (chiral,Retention Time Long)

¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (3H, s), 1.33 (3H, s), 1.51-1.60 (2H,m), 2.09 (2H, q, J=5.0 Hz), 2.56 (3H, s), 2.90 (2H, t, J=6.2 Hz),3.55-3.76 (3H, m), 3.96-4.64 (3H, m), 4.65-4.70 (1H, m), 4.79-4.83 (2H,m), 6.15-6.20 (2H, m), 6.91 (1H, s), 7.09 (1H, d, J=7.8 Hz), 7.29 (1H,d, J=8.0 Hz), 7.50-7.58 (2H, m). MS m/z 605.3 [M−H]⁺.

Example 662-[18,30-dichloro-32-methyl-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]-2-methylpropanoicAcid (Chiral, Retention Time Long)

The compounds of Examples 66 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 67[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticAcid (Chiral, Retention Time Short)

A) tert-butyl 7-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a stirred solution of 7-bromo-1,2,3,4-tetrahydroisoquinolinehydrochloride salt (25 g) in THF (400 ml) and H₂O (150 ml) were addedNa₂CO₃ (24 g) and Boc₂O (39 ml) at 25° C. and reaction mixture wasstirred at this temperature for another 16 h. After completion ofreaction (as judged by TLC), the reaction mixture was quenched with ice.The aqueous layer was extracted with EtOAc, combined organics werewashed with brine; dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude thus obtained was purified by silica gelcolumn chromatography (SiO₂, 5% EtOAc/Hexane) to give title compound (30g) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.42 (9H, s), 2.72 (2H, t, J=5.8 Hz), 3.52(2H, t, J=5.8 Hz), 4.49 (2H, s), 7.12 (1H, d, J=8.1 Hz), 7.34 (1H, d,J=8.0 Hz), 7.42 (1H, s).

B) tert-butyl7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a degassed solution of give tert-butyl7-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (20 g) in DME (90ml) was added bis(pinacolato)diboron (19 g) and potassium acetate (19 g)at 25° C. and the reaction mixture was de gassed with argon for 15 min.To this was added Pd(dppf)₂Cl₂. DCM (2.6 g) at 25° C. and the reactionmixture was stirred at 90° C. for 4 h. The mixture was filtrated, andfiltrate was concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, 10-20% EtOAc in Hexane) to give title compound (16g) as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.28 (12H, s), 1.42 (9H, s), 2.78 (2H, t,J=5.4 Hz), 3.53 (2H, t, J=5.4 Hz), 4.50 (2H, s), 7.16 (1H, d, J=7.4 Hz),7.45 (2H, m).

C) {2-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}boronicAcid

To a stirred solution of tert-butyl7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(2.00 g) in acetone (40 mL) was added NaIO₄ (3.57 g) followed byammonium acetate (1.0 M in water, 27.8 mL) at 25° C. and reactionmixture was stirred at 25° C. for 16 h. After completion of reaction (asjugged by TLC), solvent was evaporated. Residue was diluted with water.The aqueous layer was extracted with EtOAc, combined organics werewashed with brine; dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude thus obtained was purified by silica gelcolumn chromatography (SiO₂, 12 g, 50% EtOAc/Hexane) to give titlecompound (760 mg) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.42 (9H, s), 2.75-2.78 (2H, m), 3.52-3.55(2H, m), 4.48-4.54 (2H, m), 7.10-7.16 (1H, m), 7.54-7.67 (2H, m), 7.94(2H, s).

D)tert-butyl-4-[[3-[5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate

To a degassed solution of tert-butyl4-[3-[5-bromo-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate(3.7 g) in DMF (25 ml) were added ethyl acrylate (8.0 ml; 75.82 mmol)followed by DIPEA (7 ml, 37.9 mmol) at 25° C. and the reaction mixturewas degassed with argon for 10min To this was added tri-o-tolylphosphine(700 mg) and Pd(OAc)₂ (255 mg) at 25° C. and the reaction mixture washeated at 120° C. for 4 h. After completion of reaction (as judged byTLC and LC/MS), the reaction mixture was cooled to 25° C. and quenchedwith ice-water. The aqueous layer was extracted with EtOAc, combinedorganics were washed with brine; dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude thus obtained waspurified by silica gel column chromatography (SiO₂; 40 g; 30%EtOAc/Hexane) to afford title compound (3 g) as brown sticky liquid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.28 (3H, t, J=7.0 Hz), 1.53 (9H, s),2.17-2.20 (8H, m), 2.78 (3H, s), 3.39 (2H, t, J=5.5 Hz), 4.19 (2H, q,J=7.0 Hz), 4.30 (2H, s), 4.78 (2H, t, J=6.4 Hz), 6.63 (1H, d, J=15.8Hz), 6.89 (2H, s), 7.65 (1H, d, J=8.7 Hz), 7.93 (1H, d, J=8.8 Hz), 8.00(1H, d, J=12.0 Hz). MS m/z 508.2 [M+H]⁺.

E)tert-butyl-7-[1-[1-[3-[[4-[[tert-butoxy]carbonyl]-3,5-dimethylphenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

To a degassed solution oftert-butyl-4-[(3-[5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate(500 mg) in mixture of dioxane (12 ml) and water (1.2 ml) were added[2-[[tert-butoxy]carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]boronicacid (821.5 mg) followed by K₃PO₄ (626.45 mg) at 25° C. To this wasadded [RhCl(COD)]₂ (48.56 mg) at 25° C. and reaction mixture was stirredat 25° C. for 4 h under blue LED light. The reaction mixture wasquenched with sat NH₄Cl aqueous solution. The aqueous layer wasextracted with EtOAc, combined organics were washed with water, brine,dried over anhydrous Na₂SO₄, filtered and filtrate was concentratedunder reduced pressure. The crude thus obtained was purified by silicagel column chromatography (SiO₂, 12g, 40% EtOAc/Hexane) to give titlecompound (450 mg) as brown sticky solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.99 (3H, t, J=6.8 Hz), 1.40 (9H, s), 1.53(9H, s), 2.14 (2H, t, J=6.6 Hz), 2.20 (6H, s), 2.65-2.70 (2H, m), 2.77(3H, s), 3.12-3.14 (2H, m), 3.37 (2H, t, J=5.5 Hz), 3.45-3.49 (2H, m),3.89 (2H, q, J=6.5 Hz), 4.33 (2H, s), 4.41 (2H, s), 4.70 (2H, t, J=6.2Hz), 4.81 (1H, t, J=7.5 Hz), 6.94 (2H, s), 7.03 (1H, d, J=7.5 Hz),7.10-7.14 (2H, m), 7.49 (1H, d, J=8.9 Hz), 7.55 (1H, d, J=8.7 Hz).

MS m/z 741.0 [M+H]⁺.

F)4-[[3-[5-[3-ethoxy-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoicAcid

To a stirred solution oftert-butyl-7-[1-[1-[3-[[4-[[tert-butoxy]carbonyl]-3,5-dimethylphenyl]methoxy]propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(1.2 g) in DCM (40 ml) was added TFA (1.2 ml) at 25° C. The reactionmixture was stirred at 25° C. for 2 h. After completion of reaction (asjugged by LC/MS), the reaction mixture was concentrated under reducedpressure and crude was purified by reverse phase prep-HPLC (method A) togive title compound (320 mg) as off white solid.

MS m/z 585.4 [M+H]⁺.

G) ethyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]acetate

To a solution of TBTU (100.069 mg) in DMF (10 ml) was added a mixture4-[[[3-[5-[3-ethoxy-3-oxo-1-[1,2,3,4-tetrahydroisoquinolin-7-yl]propyl]-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2, 6-dimethylbenzoic acid (140 mg) in DMF (10 ml) andN,N-diisopropylethylamine (0.215 ml) by syringe pump over 1 h at 25° C.and the reaction mixture was stirred at 25° C. for 3 h. After completionof reaction (as judged by LC/MS), reaction mixture was diluted withsaturated NaHCO₃ aqueous solution. The aqueous layer was extracted withEtOAc, the combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to give titlecompound (120 mg, crude) which was used directly for next step withoutfurther purification.MS m/z 567.4 [M+H]⁺.

H)[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticAcid (Retention Time Short) and[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticAcid (Retention Time Long)

To a stirred solution ofethyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]acetate(150 mg) in a mixture of THF (3 ml) and MeOH (1.5 ml) was added 1N NaOH(1.2 ml) at 25° C. and the reaction mixture was stirred at 25° C. for 2h. After completion of reaction (as judged by TLC and LC/MS), thevolatiles were removed under reduced pressure. The crude was dissolvedin H₂O and aqueous layer was acidified with 1N HCl. The solid thusformed was filtered and finally purified by reverse phase chiralprep-HPLC (method B) to give[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticacid (retention time short, 30 mg) as grey sticky solid and[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticacid (retention time long, 30 mg) as grey sticky solid

[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticacid (retention time short)

¹H NMR (400 MHz, DMSO-d₆): δ 1.42 (3H, s), 1.85 (3H, s), 2.38 (2H, q,J=8.0 Hz), 2.93-3.08 (5H, m), 3.34 (2H, q, J=8.0 Hz), 3.64-3.68 (1H, m),3.77-3.92 (5H, m), 4.17 (1H, d, J=12.0 Hz), 4.30 (1H, d, J=12.0 Hz),4.68-4.85 (3H, m), 5.81 (1H, s), 6.15 (1H, s), 6.73 (1H, s), 7.17 (1H,d, J=8.0 Hz), 7.28 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.54 (1H,d, J=8.0 Hz), 11.54 (brs, 1H). MS m/z 539.4 [M+H]⁺.

[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticacid (retention time long)

¹H NMR (400 MHz, DMSO-d₆): δ 1.42 (3H, s), 1.85 (3H, s), 2.38 (2H, q,J=8.0 Hz), 2.93-3.08 (5H, m), 3.34 (2H, q, J=8.0 Hz), 3.64-3.68 (1H, m),3.77-3.92 (5H, m), 4.17 (1H, d, J=12.0 Hz), 4.30 (1H, d, J=12.0 Hz),4.68-4.85 (3H, m), 5.81 (1H, s), 6.15 (1H, s), 6.73 (1H, s), 7.17 (1H,d, J=8.0 Hz), 7.28 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.54 (1H,d, J=8.0 Hz), 11.49 (bs, 1H). MS m/z 539.4 [M+H]⁺.

Example 68[18,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]aceticAcid (Chiral, Retention Time Long)

The compounds of Examples 68 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Structures of Examples 1 to 68 are shown in Table 2.

Stereo EXP Name Chemical Structure chemistry MS 1 [32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18,24,27,30- decaen-2- yl]acetic acid

Racemate 509.3 2 [20-oxo-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30- decaen-2-yl]acetic acid

Racemate 495.4 3 2-(18-ethyl-32-methyl- 20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.216,19.13,7.06,10.024,28] dotriaconta-1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25- decaen-2-yl)acetic acid

Racemate 537.4 4 [33-methyl-2-oxo-7- oxa-1,15,16,17- tetrazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)] pentatriaconta-3,8,16,18(33),19,21,24,26, 31,34-decaen-23-yl]acetic acid

Racemate 551.4 5 [6,6,33-trimethyl-2-oxo- 5-oxa-1,15,16,17-[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)] pentatriaconta-3,8,16,18(33),19,21,24,26, 31,34-decaen-23-yl]acetic acid

Racemate 579.4 6 [32-methyl-20-oxo- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]propanoic acid

Diastere- omer Mixture 523.3 7 [33-methyl-2-oxo-5-oxa-1,15,16,17-tetrazaheptacyclo[22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)] pentatriaconta-3,8,16,18(33),19,21,24, 26,31,34-decaen-23- yl]acetic acid

Racemate 551.4 8 [6,6,33-trimethyl-2-oxo- 5-oxa-1,15,16,17-tetrazaheptacyclo [22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriconta- 3,8,16,18(33),19,21,24,26, 31,34-decaen-23-yl]acetic acid

Racemate 579.4 9 [18-chloro-32-methyl- 20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18- 24,27,30-decaen-2-yl]acetic acid

Racemate 543.3 10 [18-fluoro-32-methyl- 20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30,25-decaen-2-yl]aceticacid

Racemate 527.3 11 [32-methyl-20-oxo- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid <Synthesisfrom chiral ethyl [32-methyl-20- oxo-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate (Chiral,retention time short)>

Chiral 509.4 12 [32-methyl-20-oxo- 8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(16,19).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid <Synthesisfrom Chiral, Ethyl [32-methyl-20- oxo-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate (Chiral,retention time long)>

Chiral 509.3 13 [31-methyl-19-oxo- 8,9,10,20-tetrazahexacyclo[18.5.3.2^(15,18).1^(3,7).0^(6,10).0^(23,27)] hentriaconta-1(25),3(31),4,6,8,15,17, 23,26,29-decaen-2- yl)acetic acid

Racemate 495.3 14 [(13Z)-33-methyl-21- oxo-8,9,10,22-tetrazahexacyclo[20.5.3.2^(17,20).1^(3,7).0^(6,10).0^(25,29)] tritriaconta-1(27),3(33),4,6,8,13,17, 19,25,28,31-undecaen- 2-yl]acetic acid

Racemate 521.3 15 [33-methyl-21-oxo- 8,9,10,22-tetrazahexacyclo[20.5.3.2^(17,20).1^(3,7).0^(6,10).0^(25,29)]tritriaconta-1(27),3(33),4,6,8,17,19, 25,28,31-decaen-2- yl)acetic acid

Racemate 523.3 16 [32-methyl-20-oxo-14- oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 511.4 17 [18,32-dimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 525.3 18 [18-ethyl-32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 539.3 19 [18-cyclopropyl-32- methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 551.3 20 [32-methyl-20-oxo-18- (trifluoromethoxy)-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 595.3 21 [18-fluoro-32-methyl- 20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 529.3 22 [18-methoxy-32-methyl- 20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 541.3 23 [32-methyl-20-oxo-18- (trifluoromethyl)-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 579.3 24 [18-chloro-32-methyl- 20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 545.3 25 [32-methyl-20-oxo-14- oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]acetic acid <Synthesisfrom chiral ethyl [32-methyl-20- oxo-14-oxa-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate (Chiral,retention time short)>

Chiral 511.3 26 [32-methyl-20-oxo-14- oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid <Synthesisfrom chiral ethyl [32-methyl-20- oxo-14-oxa-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate (Chiral,retention time long)>

Chiral 511.3 27 ethyl 2-[32-methyl-20- oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]acetate

Racemate 539.3 28 2-methyl-2-[32-methyl- 20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]propanoicacid

Racemate 539.3 29 [32-methyl-20-oxo-13- oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 511.3 30 [32-methyl-20-oxo-15- oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 511.3 31 [18-fluoro-32-methyl- 20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 592.4 32 [18,30-difluoro-32- methyl-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetic acid

Racemate 547.4 33 [6,6,33-trimethyl-2-oxo- 7,10-dioxa-1,15,16,17-tetrazaheptacyclo [22.5.3.2^(3,9).1^(18,22).0^(4,8).0^(15,19).0^(27,31)]pentatriaconta- 3,8,16,18(33),19,21,24,26, 31,34-decaen-23- yl]aceticacid

Racemate 581.4 34 [5-methyl-2-oxo-2H-1,3-dioxol-4-yl]methyl[32-methyl-20-oxo-14- oxa-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]actate <Synthesis fromChiral, Ethyl [32- methyl-20-oxo-14-oxa- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6, 8,16,18,24,27,30- decaen-2-yl]acetate(Chiral, retention time short)>

Chiral 623.3 35 [5-methyl-2-oxo-2H- 1,3-dioxol-4-yl]methyl[32-methyl-20-oxo-14- oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]actate <Synthesis fromChiral, Ethyl [32- methyl-20-oxo-14-oxa- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8, 16,18,24,27,30-decaen-2- yl]acetate(Chiral, retention time long)>

Chiral 621.4 36 ethyl [32-methyl-20- oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-dacaen-2- yl]acetate(Chiral,retention time short)

Chiral 539.3 37 ethyl [32-methyl-20- oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate (Chiral,retention time short)

Chiral 537.4 38 2-[32-methyl-20-oxo- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]- N-[6-methylpyridin-3-yl]acetamide <Synthesis from Chiral, Ethyl [32- methyl-20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19.)1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate(Chiral, retention time short)>

Chiral 599.4 39 2-[32-methyl-20-oxo- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]- N-[pyridin-3-yl]acetamide <Synthesis from Chiral, Ethyl [32- methyl-20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate(Chiral, retention time short)>

Chiral 585.4 40 1- [[[cyclohexyloxy]carbonyl] oxy]ethyl [32-methyl-20-oxo-14-oxa- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]acetate<Synthesis from Chiral, Ethyl [32-methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate(Chiral, retention time short)>

Chiral 681.4 41 sodium [32-methyl-20- oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]acetate<Synthesis from Chiral, Ethyl [32- methyl-20-oxo-14-oxa8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]acetate(Chiral, retention time short)>

Chiral 511.3 42 2-[32-methyl-20-oxo- 14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]-N-[6-methylpyridin-3-yl]acetamide

Chiral 601.4 43 2-[18,30-dichloro-32- methyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]-2-methylpropanoic acid

Racemate 44 2-methyl-2-[32-methyl- 20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]propanoic acid

Racemate 45 2-methyl-2-[18,30,32- trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]propanoic acid

Racemate 46 2-[18,30-dichloro-32- methyl-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]-2-methylpropanoic acid

Racemate 47 2-methyl-2-[18,30,32- trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]propanoic acid

Racemate 48 2-[18,30-dichloro-25,32- dimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]- 2-methylpropanoic acid

Racemate 49 2-methyl-2-[18,25,30- trichloro-32-methyl-20-oxo-14-oxa-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2- yl]propanoic acid

Racemate 50 2-[18,30-dichloro-32- methyl-20-oxo-25-[trifluoromethyl]-14- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]- 2-methyl propanoic acid

Racemate 51 2-[8- [cyclopropylmethyl]-34- methyl-2,7-dioxo-5-oxa-1,8,16,17,18-pentazaheptacyclo[23.5.3.2^(3,10).1^(19,23).0^(4,9).0^(16,20).0^(28,32)] hexatriaconta-3,9,17,19(34),20,22,25, 27,32,35-decaen-24-yl]- 2-methylpropanoic acid

Racemate 52 2-[18,30-dichloro-32- methyl-20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]-2-methylpropanoic acid

Racemate 53 2-[18,30-dichloro-5- methoxy-20-oxo-14- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]- 2-methylpropanoic acid

Racemate 54 2-[18,30-dichloro-5- methoxy-32-methyl-20-oxo-14-oxa-8,9,10,21- tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]- 2-methylpropanoic acid

Racemate 55 2-methyl-2-[32-methyl- 20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoic acid <Chiral, synthesis from chiral methyl 2-methyl-2-[32-methyl-20-oxo- 14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6, 8,16,18,24(28),25,30-decaen-2-yl]propanoate (retention time short)>

Chiral 539.4 56 2-methyl-2-[32-methyl- 20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]propanoic acid <Chiral, synthesis from chiral methyl 2-methyl-2-[32-methyl-20-oxo- 14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6, 8,16,18,24(28),25, 30-decaen-2-yl]propanoate (retention time long)>

Chiral 539.4 57 2-[18,30-dichloro-32- methyl-20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(26),3(32),4,6,8,16,18, 24,27,30-decaen-2-yl]-2-methylpropanoic acid

Racemate 605.4 58 2-methyl-2-[18,30,32- trimethyl-20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25- decaen-2-yl]propanoicacid <Chiral, synthesis from chiral methyl 2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9, 10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8, 16,18,24(28),25,30-decaen-2-yl]propanoate (retention time short)>

Chiral 567.5 59 2-methyl-2-[18,30,32-trimethyl- 20-oxo-14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25- decaen-2-yl]propanoicacid <Chiral, synthesis from chiral methyl 2-methyl-2-[18,30,32-trimethyl-20-oxo-14-oxa-8,9, 10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16, 18,24(28),25,30-decaen-2-yl]propanoate (retention time long)>

Chiral 567.5 60 2-[18,30-dichloro-32-methyl-20- oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2-yl]-2-methylpropanoic acid <Chiral, synthesis from chiral methyl2-[18,30-dichloro-32- methyl-20-oxo-14-oxa-8,9, 10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16, 18,24(28),25,30-decaen-2-yl]-2-methylpropanoate (retention time short)>

Chiral 607.5 61 2-[18,30-dichloro-32-methyl-20- oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16, 18,24(28),25,30-decaen-2-yl]-2-methylpropanoic acid <Chiral, synthesis from chiral methyl 2-[18,30-dichloro-32-methyl-20-oxo- 14-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25, 30-decaen-2-yl]-2- methylpropanoate(retention time long)>

Chiral 607.5 62 2-methyl-2-[32-methyl- 20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25- decaen-2-yl]propanoicacid <Chiral, synthesis from chiral methyl 2-methyl-2-[32-methyl-20-oxo- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25- decaen-2-yl]propanoate(retention time short)>

Chiral 537.3 63 2-methyl-2-[32-methyl- 20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25- decaen-2-yl]propanoicacid <Chiral, synthesis from chiral methyl-2-methyl-2-[32-methyl-20-oxo- 8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)] dotriaconta-1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25- decaen-2-yl]propanoate(retention time long)>

Chiral 537.4 64 [2-[18,30-dichloro-32- methyl-20-oxo-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25-decaen-2-yl]acetyl]oxysodium

Racemate 577.4 65 2-[18,30-dichloro-32- methyl-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25-decaen-2-yl]-2- methylpropanoic acid (Chiral, retention time short

Chiral 607.5 66 2-[18,30-dichloro-32- methyl-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16(31), 17,19(30),24(28),25-decaen-2-yl]-2- methylpropanoic acid (Chiral, retention time long)

Chiral 605.3 67 [18,30,32-trimethyl-20- oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2- yl]aceticacid (Chiral, retention time short)

Chiral 539.4 68 [18,30,32-trimethyl-20- oxo-14-oxa-8,9,10,21-tetrazahexacyclo [19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta- 1(27),3(32),4,6,8,16,18, 24(28),25,30-decaen-2- yl]aceticacid (Chiral, retention time long)

Chiral 539.4

Test Example 1 Measurement of Activity of Inhibiting NRF2 Binding

The inhibitory activity of test compounds against the binding betweenNRF2 and KEAP1 was measured by Time Resolved Fluorescence ResonanceEnergy Transfer (TR-FRET) method. Into a 384 well plate, 2 μL of acompound, 2 μL of 2 nM solution of biotinylated human KEAP1 protein(Kelch domain), 2 μL of 14 nM solution of TAMRA-labeled NRF2 peptide(TAMRA-Abu(4)-VWYTDIRMRDWM-OH), and 2 μL of 2 nM solution of Tb-labeledstreptavidin, all solutions diluted with assay buffer (25 mM HEPES,pH7.5, 150 mM NaCl, 0.01% Tween-20), were added. For some wells, theKEAP1 protein was not added to define control wells. The plate wasincubated at room temperature for 60 minutes, and time-resolvedfluorescence was measured with a plate reader Envision (manufactured byPerkinElmer). The inhibitory activity for each compound at a compoundconcentration of 100 nM were calculated as a relative activity value bysetting the fluorescence intensity of control wells to which the KEAP1protein was not added as 100% inhibition, and the fluorescence intensityof wells to which no compound was added as 0%.

The measurement results according to the method described above(inhibition rate of signal value relative to control at 100 nM of testcompound) are shown in Table 3.

TABLE 3 EXP NRF2 binding inhibitory activity (at 100 nM) 1 100% 2 100% 3100% 4 100% 5 100% 6 100% 7 100% 8 100% 9 100% 10 100% 11 100% 12 100%13  99% 14  79% 15 100% 16 100% 17 100% 18 100% 19 100% 20 100% 21 100%22 100% 23 100% 24 100% 25 100% 26  99% 27  6% 28 100% 29 100% 30 100%31 100% 32 100% 33 100% 34  99% 35  99% 36  15% 37  29% 38  79% 39  97%40  82% 41 100% 42  60% 55 100% 56  99% 57 100% 58 100% 59 100% 60 100%61  99% 62 100% 63  46% 64 100% 65 100% 66  94% 67  99% 68  93%

Test Example 2 Activity of Compound on Expression of NRF2-DownstreamGene in Rat Kidney and Liver

For the NRF2-downstream gene, Nqo1 mRNA was examined in regard to theexpression level in kidney. Compounds were prepared into 0.5%methylcellulose (MC, METOLOSE, Shin-Etsu Chemical Co., Ltd.)suspensions, and were orally administered to male SD rats (CLEA Japan,Inc.) in a dose of 5 mL/kg. About 17 hours after the administration, therats were euthanized under anesthesia, and their kidneys and livers werecollected. By using an extraction kit, QIAsymphony RNA kit (QIAGEN,catalog number 931636) or RNeasy 96 Kit (QIAGEN, catalog number 74182),total RNA was extracted. From the total RNA thus obtained, cDNA wasproduced by using a cDNA synthesis kit, SuperScript IV VILO Master Mix(Thermo Fisher Scientific, catalog number 11754-250). By using the cDNAthus obtained with Taqman Fast Advanced Master Mix (Thermo FisherScientific, catalog number 4444557) or Platinum Quantitative PCRSuperMix (Thermo Fisher Scientific, catalog number 11743-500), andprimers and a probe, the sequences of which are shown in Table 4,real-time quantitative PCR was conducted with 7900HT Fast Real-Time PCRSystems or ViiA7 Fast Real-Time PCR Systems (Applied Biosystems). Theexpression level of Nqo1 mRNA in each organ of the rat to which thevehicle, 0.5% MC solution, was administered is defined as 1, and thevariation is shown in Table 5.

TABLE 4 Probe and Primer Sequences for Rat Nqo1 ProbeTCTGCGCTTCTGTGGCTTCCAGGTCT Primer_F GGGGACATGAACGTCATTCTCTG Primer_RGCCAATGCTGTACACCAGTTG

TABLE 5 Nqo1 mRNA expression (fold change Example dose (mg/kg) tissue vsvehicle) 3 3 Kidney 4.7 4 3 Kidney 6.8 5 3 Kidney 3.3 7 3 Kidney 4.3 9 3Kidney 5.5 10 3 Kidney 5.9 11 3 Kidney 8 21 3 Kidney 5 25 3 Kidney 6.5Liver 22.2 29 3 Kidney 5.9 55 3 Kidney 6.3 58 3 Kidney 4.8 60 3 Kidney2.9 62 3 Kidney 6.9 65 3 Kidney 3.6

Formulation Examples

A medicament containing the inventive compound as an active ingredientcan be produced in accordance with, for example, the followingformulation.

-   1. Capsule

(1) Compound obtained in Example 1 10 mg (2) Lactose 90 mg (3)Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule180 mg 

The whole amount of (1), (2) and (3), and 5 mg of (4) are admixed andthen granulated. To this, the remaining 5 mg of (4) is added, and thewhole is encapsulated in a gelatin capsule.

-   2. Tablet

(1) Compound obtained in Example 1 10 mg (2) Lactose 35 mg (3) Cornstarch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesiumstearate 5 mg 1 tablet 230 mg

The whole amount of (1), (2) and (3), and 20 mg of (4) and 2.5 mg of (5)are admixed and then granulated. To this granule, the remaining 10 mg of(4) and 2.5 mg of (5) are added, and the granule is pressure-molded intoa tablet.

The present invention can provide a compound that has an excellent NRF2activating activity, and is expected to be useful as a preventive ortherapeutic agent for diseases associated with oxidative stress, inparticular, hepatic disease (for example, non-alcoholic steatohepatitis(NASH)), bile duct disease (for example, primary sclerosing cholangitis(PSC)), cardiovascular disease (for example, heart failure or pulmonaryarterial hypertension), lung disease (for example, chronic obstructivepulmonary disease (COPD)), kidney disease (for example, chronic kidneydisease (CKD) or acute kidney injury (AKI)), central nervous systemdisease (for example, Parkinson's disease, Alzheimer's disease, cerebralstroke), mitochondrial disease (for example, Friedreich motor ataxia,mitochondrial myopathy), inflammatory disease (for example, multiplesclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease,cancer, or the like.

1. A compound represented by the following formula (I):

wherein R¹ is OH, ORy or NHRy; Ry is an optionally substituted C₁₋₆alkyl group or an optionally substituted cyclic group; R² and R³, whichmay be the same or different, are a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or R² and R³ are joined together to form aC₃₋₆ cycloalkyl group; X is C(═O), SO₂ or CR^(x1)R^(x2); R^(x1) and Rx²,which may be the same or different, are a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group; ring A is a benzene ring which may have anadditional substituent(s); ring B is a benzene ring which may have anadditional substituent(s); ring C is an optionally substituted 5- or6-membered aromatic ring which may contain a heteroatom(s); and L isoptionally substituted, saturated or unsaturated linear C₄₋₈ alkyleneoptionally inserted by a heteroatom, or a salt thereof.
 2. The compoundaccording to claim 1 or a salt thereof, wherein in formula (I),L is —(CR⁴R⁵)n—Y¹—(CR⁶R⁷)m—Y²—* wherein * represents attachment to ringC; n is an integer of 2 or more and 4 or less; m is an integer of 1 ormore and 4 or less; R⁴ and R⁵ are the same as or different from eachother, and are each a hydrogen atom, a halogen atom, OH, an optionallysubstituted C₁₋₆ alkyl group or an optionally substituted C₁₋₆ alkoxygroup, or R⁴ and R⁵ are joined together to form an optionallysubstituted C₃₋₆ cycloalkyl group, and a plurality of R⁴ or a pluralityof R⁵ may be the same as or different from each other, and the adjacentR⁴ or R⁵ may be joined together to form a double bond; R⁶ and R⁷ are thesame as or different from each other, and are each a hydrogen atom, ahalogen atom, OH, an optionally substituted C₁₋₆ alkyl group or anoptionally substituted C₁₋₆ alkoxy group, or R⁶ and R⁷ are joinedtogether to form an optionally substituted C₃₋₆ cycloalkyl group, andwhen m is 2 or more, a plurality of R⁶ or a plurality of R⁷ may be thesame as or different from each other, and the adjacent R⁶ or R⁷ may bejoined together to form a double bond; Y¹ and Y², which may be the sameor different, are a bond, an oxygen atom, a sulfur atom, SO, SO₂ or NR⁸,provided that when Y¹ is a bond, m is 1 or 4; and R⁸ is a hydrogen atomor an optionally substituted C₁₋₆ alkyl group, provided that when aplurality of R⁸ is present, the plurality of R⁸ may be the same as ordifferent from each other.
 3. The compound according to claim 1, or asalt thereof, wherein in formula (I), L is selected from the groupconsisting of the following formulas:—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—CR⁶R⁷—*;—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—*;—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—CR⁶R⁷—O—*;—CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—*; and—CR⁴R⁵—CR⁴R⁵—O—CR⁶R⁷—CR⁶R⁷—*.
 4. The compound according to claim 1, or asalt thereof, wherein in formula (I), R¹ is OH or ORy; Ry is a C₁₋₆alkyl group; R² and R³, which may be the same or different, are ahydrogen atom or a C₁₋₃ alkyl group; X is C(═O); ring A is a benzenering which may have an additional substituent(s) of a fluorine atom, achlorine atom, a C₁₋₃ alkyl group optionally substituted with 1 to 3substituents (selected from a halogen atom and a C₁₋₃ alkoxy group), ora C₁₋₃ alkoxy group optionally substituted with 1 to 3 substituents(selected from a halogen atom and a C₁₋₃ alkoxy group); ring B is abenzene ring which may have an additional substituent(s) of a fluorineatom, a chlorine atom, a cyano group, a C_(1.3) alkyl group optionallysubstituted with 1 to 3 substituents (selected from a halogen atom and aC₁₋₃ alkoxy group), or a C₁₋₃ alkoxy group optionally substituted with 1to 3 substituents (selected from a halogen atom and a C₁₋₃ alkoxygroup); and ring C is a group represented by the following formula:

wherein Z¹, Z², Z³, Z⁴ and Z⁵ which may be the same or different, are acarbon atom or a nitrogen atom; R^(c) is a hydrogen atom, a halogenatom, a nitro group, a cyano group, a hydroxy group, an optionallyhalogenated C₁₋₆ alkyl group, an optionally halogenated C₁₋₆ alkoxygroup, or a C₃₋₁₀ cycloalkyl group; and R^(c1), R^(c2), R^(c3) andR^(c4), which may be the same or different, are a hydrogen atom, ahalogen atom, a nitro group, a cyano group, a hydroxy group, anoptionally halogenated C₁₋₆ alkyl group, an optionally halogenated C₁₋₆alkoxy group, or a C₃₋₁₀ cycloalkyl group; or adjacent two of R^(c1),R^(c2), R^(c3) and R^(c4) may be joined together to form an optionallysubstituted ring, provided that when Z¹, Z², Z³, Z⁴ or Z⁵ is a nitrogenatom, R^(c), R^(c1), R^(c2), R^(c3) or R^(c4) is not present.
 5. Thecompound according to claim 1, or a salt thereof, wherein in formula(I), R¹ is OH; R² and R³, which may be the same or different, are ahydrogen atom or a C₁₋₃ alkyl group; X is C(═O); ring A is a benzenering which may have an additional substituent(s) of a C₁₋₃ alkyl group;ring B is a benzene ring which does not have an additionalsubstituent(s); and ring C is a group represented by the followingformula:

wherein R^(c1) and R^(c4), which may be the same or different, are ahydrogen atom, an optionally halogenated C₁₋₆ alkyl group, an optionallyhalogenated C₁₋₆ alkoxy group, a chlorine atom, or a fluorine atom, andR^(c2) and R^(c3) are each a hydrogen atom; andL is —CH₂—CH₂—CH₂—CH₂—CH₂—*,—CH₂—CH₂—CH₂—CH₂—O—*,—CH₂—CH₂—CH₂—O—CH₂—*, or—CH₂—CH₂—O—CH₂—CH₂—*.
 6. The compound according to claim 1, or a saltthereof, wherein in formula (I), R¹ is OH; R² and R³, which may be thesame or different, are a hydrogen atom or a methyl group; X is C(═O);ring A is a substructure represented by the following formula:

ring B: a benzene ring which does not have an additional substituent;ring C: a group represented by the following formula:

wherein R^(c1) and R^(c4), which may be the same or different, are ahydrogen atom, a chlorine atom, or a methyl group, and R^(c2) and R^(c3)are each a hydrogen atom; andL is —CH₂—CH₂—CH₂—CH₂—CH₂—*,—CH₂—CH₂—CH₂—CH₂—O—*,—CH₂—CH₂—CH₂—O—CH₂—*, or—CH₂—CH₂—O—CH₂—CH₂—*.
 7. A compound selected from the group consistingof the following:[32-methyl-20-oxo-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]acetic acid:

[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-l(26),3(32),4,6,8,16,18,24,27,30-decaen-2-yl]aceticacid:

2-methyl-2-[32-methyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16,18,24(28),25,30-decaen-2-yl]propionicacid:2-methyl-2[l8,30,32-trimethyl-20-oxo-14-oxa-8,9,10,21-tetraazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propionic acid:

2-methyl-2-[32-methyl-20-oxo-8,9,10,21-tetrazahexacyclo[19.5.3.2^(16,19).1^(3,7).0^(6,10).0^(24,28)]dotriaconta-1(27),3(32),4,6,8,16(31),17,19(30),24(28),25-decaen-2-yl]propanoic acid

or a salt thereof.
 8. A medicament comprising the compound according toclaim 1 or a salt thereof.
 9. The medicament according to claim 8,wherein the medicament is an NRF2 activator.
 10. The medicamentaccording to claim 8, wherein the medicament is a preventive ortherapeutic agent for hepatic and bile duct disease, cardiovasculardisease, lung disease, kidney disease, central nervous system disease,cancer, sickle cell disease, mitochondrial disease, or inflammatorydisease.
 11. A pharmaceutical composition comprising the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof foruse in prevention or treatment for hepatic and bile duct disease,cardiovascular disease, lung disease, kidney disease, central nervoussystem disease, cancer, sickle cell disease, mitochondrial disease, orinflammatory disease.
 12. A method of activating NRF2 in a mammalcomprising administering the compound according to claim 1 or a saltthereof to the mammal in an effective amount.
 13. A method of preventingor treating hepatic and bile duct disease, cardiovascular disease, lungdisease, kidney disease, central nervous system disease, cancer, sicklecell disease, mitochondrial disease, or inflammatory disease in amammal, the method comprising administering the compound according toclaim 1 or a salt thereof to the mammal.
 14. Use of the compoundaccording to claim 1 or a salt thereof for producing a preventive ortherapeutic agent for hepatic and bile duct disease, cardiovasculardisease, lung disease, kidney disease, central nervous system disease,cancer, sickle cell disease, mitochondrial disease, or inflammatorydisease.